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1.  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.
doi:10.1523/JNEUROSCI.0762-04.2004
PMCID: PMC2041891  PMID: 15306644
auditory; binaural; hearing; inferior colliculus; localization; psychophysics
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.  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
4.  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
5.  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
6.  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
7.  The Neural Representation of Interaural Time Differences in Gerbils Is Transformed from Midbrain to Cortex 
The Journal of Neuroscience  2014;34(50):16796-16808.
Interaural time differences (ITDs) are the dominant cue for the localization of low-frequency sounds. While much is known about the processing of ITDs in the auditory brainstem and midbrain, there have been relatively few studies of ITD processing in auditory cortex. In this study, we compared the neural representation of ITDs in the inferior colliculus (IC) and primary auditory cortex (A1) of gerbils. Our IC results were largely consistent with previous studies, with most cells responding maximally to ITDs that correspond to the contralateral edge of the physiological range. In A1, however, we found that preferred ITDs were distributed evenly throughout the physiological range without any contralateral bias. This difference in the distribution of preferred ITDs in IC and A1 had a major impact on the coding of ITDs at the population level: while a labeled-line decoder that considered the tuning of individual cells performed well on both IC and A1 responses, a two-channel decoder based on the overall activity in each hemisphere performed poorly on A1 responses relative to either labeled-line decoding of A1 responses or two-channel decoding of IC responses. These results suggest that the neural representation of ITDs in gerbils is transformed from IC to A1 and have important implications for how spatial location may be combined with other acoustic features for the analysis of complex auditory scenes.
doi:10.1523/JNEUROSCI.2432-14.2014
PMCID: PMC4261102  PMID: 25505332
auditory cortex; inferior colliculus; interaural time differences; population coding; spatial hearing
8.  Spatial cue reliability drives frequency tuning in the barn Owl's midbrain 
eLife  null;3:e04854.
The robust representation of the environment from unreliable sensory cues is vital for the efficient function of the brain. However, how the neural processing captures the most reliable cues is unknown. The interaural time difference (ITD) is the primary cue to localize sound in horizontal space. ITD is encoded in the firing rate of neurons that detect interaural phase difference (IPD). Due to the filtering effect of the head, IPD for a given location varies depending on the environmental context. We found that, in barn owls, at each location there is a frequency range where the head filtering yields the most reliable IPDs across contexts. Remarkably, the frequency tuning of space-specific neurons in the owl's midbrain varies with their preferred sound location, matching the range that carries the most reliable IPD. Thus, frequency tuning in the owl's space-specific neurons reflects a higher-order feature of the code that captures cue reliability.
DOI: http://dx.doi.org/10.7554/eLife.04854.001
eLife digest
The ability to locate where a sound is coming from is an essential survival skill for both prey and predator species. A major cue used by the brain to infer the sound's location is the difference in arrival time of the sound at the left and right ears; for example, a sound coming from the left side will reach the left ear before the right ear.
We are exposed to a variety of sounds of different intensities (loud or soft), and pitch (high or low) emitted from many different directions. The cacophony that surrounds us makes it a challenge to detect where individual sounds come from because other sounds from different directions corrupt the signals coming from the target. This background noise can profoundly affect the reliability of the sensory cue.
When sounds reach the ears, the head and external ears transform the sound in a direction-dependent manner so that some pitches are amplified more than other pitches for specific directions. However, the consequence of this filtering is that the directional information about a sound may be altered. For example, if two sounds of a similar pitch but from different locations are heard at the same time, they will add up at the ears and change the directional information. The group of neurons that respond to that range of pitches will be activated by both sounds so they cannot provide reliable information about the direction of the individual sounds. The degree to which the directional information is altered depends on the pitch that is being detected by the neurons; therefore detection of a different pitch within the sound may be a more reliable cue.
Cazettes et al. used the known filtering properties of the owl's head to predict the reliability of the timing cue for sounds coming from different directions in a noisy environment. This analysis showed that for each direction, there was a range of pitches that carried the most reliable cues. The study then focused on whether the neurons that represent hearing space in the owl's brain were sensitive to this range.
The experiments found a remarkable correlation between the pitch preferred by each neuron and the range that carried the most reliable cue for each direction. This finding challenges the common view of sensory neurons as simple processors by showing that they are also selective to high-order properties relating to the reliability of the cue.
Besides selecting the cues that are likely to be the most reliable, the brain must capture changes in the reliability of the sensory cues. In addition, this reliability must be incorporated into the information carried by neurons and used when deciding how best to act in uncertain situations. Future research will be required to unravel how the brain does this.
DOI: http://dx.doi.org/10.7554/eLife.04854.002
doi:10.7554/eLife.04854
PMCID: PMC4291741  PMID: 25531067
barn owl; neural coding; cue reliability; sound localization; other
9.  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.
doi:10.1152/jn.00751.2007
PMCID: PMC2570106  PMID: 18287556
10.  The effects of interaural time difference and intensity on the coding of low frequency sounds in the mammalian midbrain 
We examined how changes in intensity and interaural time difference (ITD) influenced the coding of low frequency sounds in the inferior colliculus (IC) of male gerbils at both the single neuron and population levels. We found that changes in intensity along the positive slope of the rate-level function (RLF) evoked changes in spectrotemporal filtering that influenced in the overall timing of spike events, but preserved their precision across trials such that the decoding of single neuron responses was not affected. In contrast, changes in ITD did not trigger changes in spectrotemporal filtering, but had strong effects on the precision of spike events and, consequently, on decoder performance. However, changes in ITD had opposing effects in the two brain hemispheres, and, thus, canceled out at the population level. These results were similar with and without the addition of background noise. We also found that the effects of changes in intensity along the negative slope of the rate-level function (RLF) were different from the effects of changes in intensity along the positive slope in that they evoked changes in both spectrotemporal filtering and in the precision of spike events across trials, as well as in decoder performance. These results demonstrate that, at least at moderate intensities, the auditory system employs different strategies at the single neuron and population levels simultaneously to ensure that the coding of sounds is robust to changes in other stimulus features.
doi:10.1523/JNEUROSCI.4806-10.2011
PMCID: PMC3083843  PMID: 21389237
auditory; coding; decoding; spectrotemporal filtering; ITD; midbrain
11.  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.
doi:10.1523/JNEUROSCI.0220-06.2006
PMCID: PMC2492673  PMID: 16738236
interaural time difference; sound localization; inferior colliculus; nucleus laminaris; barn owl; pooling
12.  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
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.
doi:10.1152/jn.00833.2005
PMCID: PMC2532520  PMID: 16424454
14.  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
15.  The Opponent Channel Population Code of Sound Location Is an Efficient Representation of Natural Binaural Sounds 
PLoS Computational Biology  2015;11(5):e1004294.
In mammalian auditory cortex, sound source position is represented by a population of broadly tuned neurons whose firing is modulated by sounds located at all positions surrounding the animal. Peaks of their tuning curves are concentrated at lateral position, while their slopes are steepest at the interaural midline, allowing for the maximum localization accuracy in that area. These experimental observations contradict initial assumptions that the auditory space is represented as a topographic cortical map. It has been suggested that a “panoramic” code has evolved to match specific demands of the sound localization task. This work provides evidence suggesting that properties of spatial auditory neurons identified experimentally follow from a general design principle- learning a sparse, efficient representation of natural stimuli. Natural binaural sounds were recorded and served as input to a hierarchical sparse-coding model. In the first layer, left and right ear sounds were separately encoded by a population of complex-valued basis functions which separated phase and amplitude. Both parameters are known to carry information relevant for spatial hearing. Monaural input converged in the second layer, which learned a joint representation of amplitude and interaural phase difference. Spatial selectivity of each second-layer unit was measured by exposing the model to natural sound sources recorded at different positions. Obtained tuning curves match well tuning characteristics of neurons in the mammalian auditory cortex. This study connects neuronal coding of the auditory space with natural stimulus statistics and generates new experimental predictions. Moreover, results presented here suggest that cortical regions with seemingly different functions may implement the same computational strategy-efficient coding.
Author Summary
Ability to localize the position of a sound source is vital to many organisms, since audition provides information about areas which are not accessible visually. While its importance is undisputed, its neuronal mechanisms are not well understood. It has been observed in experimental studies that despite the crucial role of sound localization, single neurons in the auditory cortex of mammals carry very little information about the sound position. The joint activity of multiple neurons is required to accurately localize sound, and it is an open question how this computation is performed by auditory cortical circuits. In this work I propose a statistical model of natural stereo sounds. The model is based on the theoretical concept of sparse, efficient coding which has provided candidate explanations of how different sensory systems may work. When adapted to binaural sounds recorded in a natural environment, the model reveals properties highly similar to those of neurons in the mammalian auditory cortex, suggesting that mechanisms of neuronal auditory coding can be understood in terms of general, theoretical principles.
doi:10.1371/journal.pcbi.1004294
PMCID: PMC4440638  PMID: 25996373
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.  Neural tuning matches frequency-dependent time differences between the ears 
eLife  null;4:e06072.
The time it takes a sound to travel from source to ear differs between the ears and creates an interaural delay. It varies systematically with spatial direction and is generally modeled as a pure time delay, independent of frequency. In acoustical recordings, we found that interaural delay varies with frequency at a fine scale. In physiological recordings of midbrain neurons sensitive to interaural delay, we found that preferred delay also varies with sound frequency. Similar observations reported earlier were not incorporated in a functional framework. We find that the frequency dependence of acoustical and physiological interaural delays are matched in key respects. This suggests that binaural neurons are tuned to acoustical features of ecological environments, rather than to fixed interaural delays. Using recordings from the nerve and brainstem we show that this tuning may emerge from neurons detecting coincidences between input fibers that are mistuned in frequency.
DOI: http://dx.doi.org/10.7554/eLife.06072.001
eLife digest
When you hear a sound, such as someone calling your name, it is often possible to make a good estimate of where that sound came from. If the sound came from the left, it would reach your left ear before your right ear, and vice versa if the sound originated from your right. The time that passes between the sound reaching each ear is known as the ‘interaural time difference’. Previous research has suggested that specific neurons in the brain respond to specific interaural time differences, and the brain then uses this interaural time difference to locate the sound.
Sounds come in various frequencies from high-pitched alarms to low bass tones, and how a neuron responds to interaural time differences appears to change according to the frequency of the sound being played. For example, a given neuron may respond to a 200- microsecond interaural time difference when a tone is played at a high frequency, but show no response to this time difference when the tone is played at a low frequency. To date, researchers had been unable to explain why this occurs.
Here, Benichoux et al. investigated this topic by playing a variety of sounds to anaesthetized cats. Electrodes were used to record the responses of individual neurons in the cats' brains, and the properties of the sound waves that reached the cats' ears were also recorded. These experiments revealed that the time it took a sound to travel from a location to each of the cats' ears, and consequently the interaural time difference, depended on whether it was a high-pitched or a low-pitched sound. This happened because different properties of the environment, such as the angle of the cat's head, affected specific frequencies in different ways.
As expected, the neurons' responses were also affected by sound frequency. Indeed, the neurons' behaviour mirrored that of the sound waves themselves. This shows that neurons do not, as previously thought, simply react to specific interaural differences. Instead, these neurons use both sound frequency and interaural time differences to produce a thorough approximation of the sound's location. The precise mechanisms that generate this brain adaptation to the animal's environment remain to be determined.
DOI: http://dx.doi.org/10.7554/eLife.06072.002
doi:10.7554/eLife.06072
PMCID: PMC4439524  PMID: 25915620
electrophysiology; auditory brainstem; cat; other
18.  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
19.  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.
doi:10.3389/fncir.2012.00045
PMCID: PMC3394089  PMID: 22798945
sound localization; central nucleus of the inferior colliculus; auditory; plasticity; adaptation; interaural time difference; interaural level difference; frequency tuning
20.  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
21.  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.
doi:10.1371/journal.pone.0008015
PMCID: PMC2776990  PMID: 19956693
22.  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
23.  Interplay between low threshold voltage-gated K+ channels and synaptic inhibition in neurons of the chicken nucleus laminaris along its frequency axis 
Central auditory neurons that localize sound in horizontal space have specialized intrinsic and synaptic cellular mechanisms to tightly control the threshold and timing for action potential generation. However, the critical interplay between intrinsic voltage-gated conductances and extrinsic synaptic conductances in determining neuronal output are not well understood. In chicken, neurons in the nucleus laminaris (NL) encode sound location using interaural time difference (ITD) as a cue. Along the tonotopic axis of NL, there exist robust differences among low, middle, and high frequency (LF, MF, and HF, respectively) neurons in a variety of neuronal properties such as low threshold voltage-gated K+ (LTK) channels and depolarizing inhibition. This establishes NL as an ideal model to examine the interactions between LTK currents and synaptic inhibition across the tonotopic axis. Using whole-cell patch clamp recordings prepared from chicken embryos (E17–E18), we found that LTK currents were larger in MF and HF neurons than in LF neurons. Kinetic analysis revealed that LTK currents in MF neurons activated at lower voltages than in LF and HF neurons, whereas the inactivation of the currents was similar across the tonotopic axis. Surprisingly, blockade of LTK currents using dendrotoxin-I (DTX) tended to broaden the duration and increase the amplitude of the depolarizing inhibitory postsynaptic potentials (IPSPs) in NL neurons without dependence on coding frequency regions. Analyses of the effects of DTX on inhibitory postsynaptic currents led us to interpret this unexpected observation as a result of primarily postsynaptic effects of LTK currents on MF and HF neurons, and combined presynaptic and postsynaptic effects in LF neurons. Furthermore, DTX transferred subthreshold IPSPs to spikes. Taken together, the results suggest a critical role for LTK currents in regulating inhibitory synaptic strength in ITD-coding neurons at various frequencies.
doi:10.3389/fncir.2014.00051
PMCID: PMC4033047  PMID: 24904297
GABAergic inhibition; voltage-gated low-threshold potassium current; IPSC; IPSP; tonotopy; whole-cell patch; interaural time difference
24.  Difference in response reliability predicted by spectrotemporal tuning in the cochlear nuclei of barn owls 
The brainstem auditory pathway is obligatory for all aural information. Brainstem auditory neurons must encode the level and timing of sounds, as well as their time-dependent spectral properties, the fine structure and envelope, which are essential for sound discrimination. This study focused on envelope coding in the two cochlear nuclei of the barn owl, nucleus angularis (NA) and nucleus magnocellularis (NM). NA and NM receive input from bifurcating auditory nerve fibers and initiate processing pathways specialized in encoding interaural time (ITD) and level (ILD) differences, respectively. We found that NA neurons, though unable to accurately encode stimulus phase, lock more strongly to the stimulus envelope than NM units. The spectrotemporal receptive fields (STRFs) of NA neurons exhibit a pre-excitatory suppressive field. Using multilinear regression analysis and computational modeling, we show that this feature of STRFs can account for enhanced across-trial response reliability, by locking spikes to the stimulus envelope. Our findings indicate a dichotomy in envelope coding between the time and intensity processing pathways as early as at the level of the cochlear nuclei. This allows the ILD processing pathway to encode envelope information with greater fidelity than the ITD processing pathway. Furthermore, we demonstrate that the properties of the neurons’ STRFs can be quantitatively related to spike timing reliability.
doi:10.1523/JNEUROSCI.5422-10.2011
PMCID: PMC3059808  PMID: 21368035
Nucleus angularis; STRF; spectrotemporal tuning; cochlear nuclei; barn owl; response reliability
25.  The Interaural Time Difference Pathway: a Comparison of Spectral Bandwidth and Correlation Sensitivity at Three Anatomical Levels 
ABSTRACT
Temporal differences between the two ears are critical for spatial hearing. They can be described along axes of interaural time difference (ITD) and interaural correlation, and their processing starts in the brainstem with the convergence of monaural pathways which are tuned in frequency and which carry temporal information. In previous studies, we examined the bandwidth (BW) of frequency tuning at two stages: the auditory nerve (AN) and inferior colliculus (IC), and showed that BW depends on characteristic frequency (CF) but that there is no difference in the mean BW of these two structures when measured in a binaural, temporal framework. This suggested that there is little frequency convergence in the ITD pathway between AN and IC and that frequency selectivity determined by the cochlear filter is preserved up to the IC. Unexpectedly, we found that AN and IC neurons can be similar in CF and BW, yet responses to changes in interaural correlation in the IC were different than expected from coincidence patterns (“pseudo-binaural” responses) in the AN. To better understand this, we here examine the responses of bushy cells, which provide monaural inputs to binaural neurons. Using broadband noise, we measured BW and correlation sensitivity in the cat trapezoid body (TB), which contains the axons of bushy cells. This allowed us to compare these two metrics at three stages in the ITD pathway. We found that BWs in the TB are similar to those in the AN and IC. However, TB neurons were found to be more sensitive to changes in stimulus correlation than AN or IC neurons. This is consistent with findings that show that TB fibers are more temporally precise than AN fibers, but is surprising because it suggests that the temporal information available monaurally is not fully exploited binaurally.
doi:10.1007/s10162-013-0436-6
PMCID: PMC3946137  PMID: 24402167
binaural; temporal; bandwidth; interaural time difference; bushy cell; cochlear nucleus

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