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1.  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.
PMCID: PMC2719282  PMID: 19396457
Barn owl; Interaural time difference; Cross-correlation; Coincidence detection; Cochlear delays; Sound localization; Nucleus laminaris; Stereausis
2.  Emergence of Multiplicative Auditory Responses in the Midbrain of the Barn Owl 
Journal of neurophysiology  2007;98(3):1181-1193.
Space-specific neurons in the barn owl’s auditory space map gain spatial selectivity through tuning to combinations of the interaural time difference (ITD) and interaural level difference (ILD). The combination of ITD and ILD in the subthreshold responses of space-specific neurons in the external nucleus of the inferior colliculus (ICx) is well described by a multiplication of ITD- and ILD-dependent components. It is unknown, however, how ITD and ILD are combined at the site of ITD and ILD convergence in the lateral shell of the central nucleus of the inferior colliculus (ICcl) and therefore whether ICx is the first site in the auditory pathway where multiplicative tuning to ITD-and ILD-dependent signals occurs. We used extracellular re-cording of single neurons to determine how ITD and ILD are combined in ICcl of the anesthetized barn owl (Tyto alba). A comparison of additive, multiplicative, and linear-threshold models of neural responses shows that ITD and ILD are combined nonlinearly in ICcl, but the interaction of ITD and ILD is not uniformly multiplicative over the sample. A subset (61%) of the neural responses is well described by the multiplicative model, indicating that ICcl is the first site where multiplicative tuning to ITD- and ILD-dependent signals occurs. ICx, however, is the first site where multiplicative tuning is observed consistently. A network model shows that a linear combination of ICcl responses to ITD–ILD pairs is sufficient to produce the multiplicative subthreshold responses to ITD and ILD seen in ICx.
PMCID: PMC2532518  PMID: 17615132
3.  Detection of Large Interaural Delays and Its Implication for Models of Binaural Interaction  
The interaural time difference (ITD) is a major cue to sound localization along the horizontal plane. The maximum natural ITD occurs when a sound source is positioned opposite to one ear. We examined the ability of owls and humans to detect large ITDs in sounds presented through headphones. Stimuli consisted of either broad or narrow bands of Gaussian noise, 100 ms in duration. Using headphones allowed presentation of ITDs that are greater than the maximum natural ITD. Owls were able to discriminate a sound leading to the left ear from one leading to the right ear, for ITDs that are 5 times the maximum natural delay. Neural recordings from optic-tectum neurons, however, show that best ITDs are usually well within the natural range and are never as large as ITDs that are behaviorally discriminable. A model of binaural cross-correlation with short delay lines is shown to explain behavioral detection of large ITDs. The model uses curved trajectories of a cross-correlation pattern as the basis for detection. These trajectories represent side peaks of neural ITD-tuning curves and successfully predict localization reversals by both owls and human subjects.
PMCID: PMC3202365  PMID: 12083726
interaural; binaural; owl; ITD
4.  The representation of sound localization cues in the barn owl's inferior colliculus 
The barn owl is a well-known model system for studying auditory processing and sound localization. This article reviews the morphological and functional organization, as well as the role of the underlying microcircuits, of the barn owl's inferior colliculus (IC). We focus on the processing of frequency and interaural time (ITD) and level differences (ILD). We first summarize the morphology of the sub-nuclei belonging to the IC and their differentiation by antero- and retrograde labeling and by staining with various antibodies. We then focus on the response properties of neurons in the three major sub-nuclei of IC [core of the central nucleus of the IC (ICCc), lateral shell of the central nucleus of the IC (ICCls), and the external nucleus of the IC (ICX)]. ICCc projects to ICCls, which in turn sends its information to ICX. The responses of neurons in ICCc are sensitive to changes in ITD but not to changes in ILD. The distribution of ITD sensitivity with frequency in ICCc can only partly be explained by optimal coding. We continue with the tuning properties of ICCls neurons, the first station in the midbrain where the ITD and ILD pathways merge after they have split at the level of the cochlear nucleus. The ICCc and ICCls share similar ITD and frequency tuning. By contrast, ICCls shows sigmoidal ILD tuning which is absent in ICCc. Both ICCc and ICCls project to the forebrain, and ICCls also projects to ICX, where space-specific neurons are found. Space-specific neurons exhibit side peak suppression in ITD tuning, bell-shaped ILD tuning, and are broadly tuned to frequency. These neurons respond only to restricted positions of auditory space and form a map of two-dimensional auditory space. Finally, we briefly review major IC features, including multiplication-like computations, correlates of echo suppression, plasticity, and adaptation.
PMCID: PMC3394089  PMID: 22798945
sound localization; central nucleus of the inferior colliculus; auditory; plasticity; adaptation; interaural time difference; interaural level difference; frequency tuning
5.  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.
PMCID: PMC2532515  PMID: 17314241
6.  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.
PMCID: PMC3821004  PMID: 24265615
phase-locking; sound localization; auditory brainstem; periodic signals; oscillation; owl
7.  A Physiologically Based Model of Interaural Time Difference Discrimination 
Interaural time difference (ITD) is a cue to the location of sounds containing low frequencies and is represented in the inferior colliculus (IC) by cells that respond maximally at a particular best delay (BD). Previous studies have demonstrated that single ITD-sensitive cells contain sufficient information in their discharge patterns to account for ITD acuity on the midline (ITD = 0). If ITD discrimination were based on the activity of the most sensitive cell available (“lower envelope hypothesis”), then ITD acuity should be relatively constant as a function of ITD. In response to broadband noise, however, the ITD acuity of human listeners degrades as ITD increases. To account for these results, we hypothesize that pooling of information across neurons is an essential component of ITD discrimination. This report describes a neural pooling model of ITD discrimination based on the response properties of ITD-sensitive cells in the IC of anesthetized cats.
Rate versus ITD curves were fit with a cross-correlation model of ITD sensitivity, and the parameters were used to constrain a population model of ITD discrimination. The model accurately predicts ITD acuity as a function of ITD for broadband noise stimuli when responses are pooled across best frequency (BF). Furthermore, ITD tuning based solely on a system of internal delays is not sufficient to predict ITD acuity in response to 500 Hz tones, suggesting that acuity is likely refined by additional mechanisms. The physiological data confirms evidence from the guinea pig that BD varies systematically with BF, generalizing the observation across species.
PMCID: PMC2041891  PMID: 15306644
auditory; binaural; hearing; inferior colliculus; localization; psychophysics
8.  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.
PMCID: PMC2822993  PMID: 20053889
Sound; Localization; Auditory; Brainstem; Axon; Conduction; Velocity
9.  Noise Reduction of Coincidence Detector Output by the Inferior Colliculus of the Barn Owl 
A recurring theme in theoretical work is that integration over populations of similarly tuned neurons can reduce neural noise. However, there are relatively few demonstrations of an explicit noise reduction mechanism in a neural network. Here we demonstrate that the brainstem of the barn owl includes a stage of processing apparently devoted to increasing the signal-to-noise ratio in the encoding of the interaural time difference (ITD), one of two primary binaural cues used to compute the position of a sound source in space. In the barn owl, the ITD is processed in a dedicated neural pathway that terminates at the core of the inferior colliculus (ICcc). The actual locus of the computation of the ITD is before ICcc in the nucleus laminaris (NL), and ICcc receives no inputs carrying information that did not originate in NL. Unlike in NL, the rate-ITD functions of ICcc neurons require as little as a single stimulus presentation per ITD to show coherent ITD tuning. ICcc neurons also displayed a greater dynamic range with a maximal difference in ITD response rates approximately double that seen in NL. These results indicate that ICcc neurons perform a computation functionally analogous to averaging across a population of similarly tuned NL neurons.
PMCID: PMC2492673  PMID: 16738236
interaural time difference; sound localization; inferior colliculus; nucleus laminaris; barn owl; pooling
10.  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.
PMCID: PMC2948976  PMID: 16435285
avian; nucleus laminaris; nucleus magnocellularis; dendrite; coincidence detection; sound localization
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.
PMCID: PMC3157295  PMID: 21414923
12.  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.
PMCID: PMC2893945  PMID: 20613857
13.  Comparison of Midbrain and Thalamic Space-Specific Neurons in Barn Owls 
Journal of neurophysiology  2006;95(2):783-790.
Spatial receptive fields of neurons in the auditory pathway of the barn owl result from the sensitivity to combinations of interaural time (ITD) and level differences across stimulus frequency. Both the forebrain and tectum of the owl contain such neurons. The neural pathways, which lead to the forebrain and tectal representations of auditory space, separate before the midbrain map of auditory space is synthesized. The first nuclei that belong exclusively to either the forebrain or the tectal pathways are the nucleus ovoidalis (Ov) and the external nucleus of the inferior colliculus (ICx), respectively. Both receive projections from the lateral shell subdivision of the inferior colliculus but are not interconnected. Previous studies indicate that the owl’s tectal representation of auditory space is different from those found in the owl’s forebrain and the mammalian brain. We addressed the question of whether the computation of spatial cues in both pathways is the same by comparing the ITD tuning of Ov and ICx neurons. Unlike in ICx, the relationship between frequency and ITD tuning had not been studied in single Ov units. In contrast to the conspicuous frequency independent ITD tuning of space-specific neurons of ICx, ITD selectivity varied with frequency in Ov. We also observed that the spatially tuned neurons of Ov respond to lower frequencies and are more broadly tuned to ITD than in ICx. Thus there are differences in the integration of frequency and ITD in the two sound-localization pathways. Thalamic neurons integrate spatial information not only within a broader frequency band but also across ITD channels.
PMCID: PMC2532520  PMID: 16424454
14.  Cross Correlation by Neurons of the Medial Superior Olive: a Reexamination 
Initial analysis of interaural temporal disparities (ITDs), a cue for sound localization, occurs in the superior olivary complex. The medial superior olive (MSO) receives excitatory input from the left and right cochlear nuclei. Its neurons are believed to be coincidence detectors, discharging when input arrives simultaneously from the two sides. Many current psychophysical models assume a strict version of coincidence, in which neurons of the MSO cross correlate their left and right inputs. However, there have been few tests of this assumption. Here we examine data derived from two earlier studies of the MSO and compare the responses to the output of a computational model. We find that the MSO is not an ideal cross correlator. Ideal cross correlation implies a strict relationship between the precision of phase-locking of the inputs and the range of ITDs to which a neuron responds. This relationship does not appear to be met. Instead, the modeling implies that a neuron responds over a wider range of ITDs than expected from the inferred precision of phase-locking of the inputs. The responses are more consistent with a scheme in which the neuron can also be activated by the input from one side alone. Such activation degrades the tuning of neurons in the MSO to ITDs.
PMCID: PMC2504554  PMID: 15492883
auditory neurophysiology; binaural hearing; interaural time differences; coincidence detection; phase-locking
15.  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.
PMCID: PMC4024823  PMID: 24804642
16.  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.
PMCID: PMC3170859  PMID: 18491165
Auditory; Hearing; Sound localization; Sensory
17.  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.
PMCID: PMC4143899  PMID: 25206329
sound localization; interaural time differences; avian brainstem; nucleus laminaris; ITD resolution
18.  Multiplicative Auditory Spatial Receptive Fields Created by a Hierarchy of Population Codes 
PLoS ONE  2009;4(11):e8015.
A multiplicative combination of tuning to interaural time difference (ITD) and interaural level difference (ILD) contributes to the generation of spatially selective auditory neurons in the owl's midbrain. Previous analyses of multiplicative responses in the owl have not taken into consideration the frequency-dependence of ITD and ILD cues that occur under natural listening conditions. Here, we present a model for the responses of ITD- and ILD-sensitive neurons in the barn owl's inferior colliculus which satisfies constraints raised by experimental data on frequency convergence, multiplicative interaction of ITD and ILD, and response properties of afferent neurons. We propose that multiplication between ITD- and ILD-dependent signals occurs only within frequency channels and that frequency integration occurs using a linear-threshold mechanism. The model reproduces the experimentally observed nonlinear responses to ITD and ILD in the inferior colliculus, with greater accuracy than previous models. We show that linear-threshold frequency integration allows the system to represent multiple sound sources with natural sound localization cues, whereas multiplicative frequency integration does not. Nonlinear responses in the owl's inferior colliculus can thus be generated using a combination of cellular and network mechanisms, showing that multiple elements of previous theories can be combined in a single system.
PMCID: PMC2776990  PMID: 19956693
19.  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.
PMCID: PMC3170862  PMID: 19553438
20.  Neural Computation via Neural Geometry: A Place Code for Inter-whisker Timing in the Barrel Cortex? 
PLoS Computational Biology  2011;7(10):e1002188.
The place theory proposed by Jeffress (1948) is still the dominant model of how the brain represents the movement of sensory stimuli between sensory receptors. According to the place theory, delays in signalling between neurons, dependent on the distances between them, compensate for time differences in the stimulation of sensory receptors. Hence the location of neurons, activated by the coincident arrival of multiple signals, reports the stimulus movement velocity. Despite its generality, most evidence for the place theory has been provided by studies of the auditory system of auditory specialists like the barn owl, but in the study of mammalian auditory systems the evidence is inconclusive. We ask to what extent the somatosensory systems of tactile specialists like rats and mice use distance dependent delays between neurons to compute the motion of tactile stimuli between the facial whiskers (or ‘vibrissae’). We present a model in which synaptic inputs evoked by whisker deflections arrive at neurons in layer 2/3 (L2/3) somatosensory ‘barrel’ cortex at different times. The timing of synaptic inputs to each neuron depends on its location relative to sources of input in layer 4 (L4) that represent stimulation of each whisker. Constrained by the geometry and timing of projections from L4 to L2/3, the model can account for a range of experimentally measured responses to two-whisker stimuli. Consistent with that data, responses of model neurons located between the barrels to paired stimulation of two whiskers are greater than the sum of the responses to either whisker input alone. The model predicts that for neurons located closer to either barrel these supralinear responses are tuned for longer inter-whisker stimulation intervals, yielding a topographic map for the inter-whisker deflection interval across the surface of L2/3. This map constitutes a neural place code for the relative timing of sensory stimuli.
Author Summary
To perceive how stimuli move over sensor surfaces like the retina or the fingertips, neurons in the brain must report the relative timing of signals arriving at different locations on the sensor surface. The rat whisker system is ideal for exploring how the brain performs this computation, because the layout of a small number of sensors (whiskers) maps directly onto the layout of corresponding columns of neurons in the sensory cortex. Previous studies have found that neurons located between adjacent cortical columns are most likely to respond when the corresponding adjacent whiskers are stimulated in rapid succession. These results suggest a link between the location of the neuron and the relative timing of sensory signals reported by its activity. We hypothesized that, if the time taken for whisker signals to arrive at a neuron is related to its distance from each cortical column, then neurons closer to a particular column will report stimuli moving towards that particular whisker. In a model approximating the geometry of cortical connections, responses of artificial neurons matched those of real neurons on a wide range of details. These results suggest an important role for neural geometry in neural computation.
PMCID: PMC3192806  PMID: 22022245
21.  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.
PMCID: PMC3025489  PMID: 20962228
binaural hearing; electric stimulation; congenital deafness; cochlear implant; inferior colliculus; ITD
22.  Coincidence detection in the medial superior olive: mechanistic implications of an analysis of input spiking patterns 
Coincidence detection by binaural neurons in the medial superior olive underlies sensitivity to interaural time difference (ITD) and interaural correlation (ρ). It is unclear whether this process is akin to a counting of individual coinciding spikes, or rather to a correlation of membrane potential waveforms resulting from converging inputs from each side. We analyzed spike trains of axons of the cat trapezoid body (TB) and auditory nerve (AN) in a binaural coincidence scheme. ITD was studied by delaying “ipsi-” vs. “contralateral” inputs; ρ was studied by using responses to different noises. We varied the number of inputs; the monaural and binaural threshold and the coincidence window duration. We examined physiological plausibility of output “spike trains” by comparing their rate and tuning to ITD and ρ to those of binaural cells. We found that multiple inputs are required to obtain a plausible output spike rate. In contrast to previous suggestions, monaural threshold almost invariably needed to exceed binaural threshold. Elevation of the binaural threshold to values larger than 2 spikes caused a drastic decrease in rate for a short coincidence window. Longer coincidence windows allowed a lower number of inputs and higher binaural thresholds, but decreased the depth of modulation. Compared to AN fibers, TB fibers allowed higher output spike rates for a low number of inputs, but also generated more monaural coincidences. We conclude that, within the parameter space explored, the temporal patterns of monaural fibers require convergence of multiple inputs to achieve physiological binaural spike rates; that monaural coincidences have to be suppressed relative to binaural ones; and that the neuron has to be sensitive to single binaural coincidences of spikes, for a number of excitatory inputs per side of 10 or less. These findings suggest that the fundamental operation in the mammalian binaural circuit is coincidence counting of single binaural input spikes.
PMCID: PMC4013490  PMID: 24822037
medial superior olive; auditory nerve; input convergence; coincidence window; interaural time difference; interaural correlation; temporal coding; coincidence detection
23.  Sensitivity of Inferior Colliculus Neurons to Interaural Time Differences in the Envelope Versus the Fine Structure With Bilateral Cochlear Implants 
Journal of neurophysiology  2008;99(5):2390-2407.
Bilateral cochlear implantation seeks to improve hearing by taking advantage of the binaural processing of the central auditory system. Cochlear implants typically encode sound in each spectral channel by amplitude modulating (AM) a fixed-rate pulse train, thus interaural time differences (ITD) are only delivered in the envelope. We investigated the ITD sensitivity of inferior colliculus (IC) neurons with sinusoidally AM pulse trains. ITD was introduced independently to the AM and/or carrier pulses to measure the relative efficacy of envelope and fine structure for delivering ITD information. We found that many IC cells are sensitive to ITD in both the envelope (ITDenv) and fine structure (ITDfs) for appropriate modulation frequencies and carrier rates. ITDenv sensitivity was generally similar to that seen in normal-hearing animals with AM tones. ITDenv tuning generally improved with increasing modulation frequency up to the maximum modulation frequency that elicited a sustained response in a neuron (tested ≤Hz). ITDfs sensitivity was present in about half the neurons for 1,000 pulse/s (pps) carriers and was nonexistent at 5,000 pps. The neurons that were sensitive to ITDfs at 1,000 pps were those that showed the best ITD sensitivity to low-rate pulse trains. Overall, the best ITD sensitivity was found for ITD contained in the fine structure of a moderate rate AM pulse train (1,000 pps). These results suggest that the interaural timing of current pulses should be accurately controlled in a bilateral cochlear implant processing strategy that provides salient ITD cues.
PMCID: PMC2570106  PMID: 18287556
24.  Binaural Gain Modulation of Spectrotemporal Tuning in the Interaural Level Difference-Coding Pathway 
The Journal of Neuroscience  2013;33(27):11089-11099.
In the brainstem, the auditory system diverges into two pathways that process different sound localization cues, interaural time differences (ITDs) and level differences (ILDs). We investigated the site where ILD is detected in the auditory system of barn owls, the posterior part of the lateral lemniscus (LLDp). This structure is equivalent to the lateral superior olive in mammals. The LLDp is unique in that it is the first place of binaural convergence in the brainstem where monaural excitatory and inhibitory inputs converge. Using binaurally uncorrelated noise and a generalized linear model, we were able to estimate the spectrotemporal tuning of excitatory and inhibitory inputs to these cells. We show that the response of LLDp neurons is highly locked to the stimulus envelope. Our data demonstrate that spectrotemporally tuned, temporally delayed inhibition enhances the reliability of envelope locking by modulating the gain of LLDp neurons' responses. The dependence of gain modulation on ILD shown here constitutes a means for space-dependent coding of stimulus identity by the initial stages of the auditory pathway.
PMCID: PMC3718367  PMID: 23825414
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.
PMCID: PMC2041852  PMID: 17581961
binaural hearing; electric stimulation; neural prosthesis; cochlear implant; inferior colliculus; ITD

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