Interaural Time Difference Tuning Research Articles

Neonatal Deafening Selectively Degrades the Sensitivity to Interaural Time Differences of Electrical Stimuli in Low-Frequency Pathways in Rats.

We examined the effect of neonatal deafening on frequency-specific pathways for processing of interaural time differences (ITDs) in cochlear-implant stimuli. Animal studies have demonstrated differences in neural ITD sensitivity in the inferior colliculus (IC) depending on the intracochlear location of intracochlear stimulating electrodes. We used neonatally deafened (ND) rats of both sexes and recorded the responses of single neurons in the IC to electrical stimuli with ITDs delivered to the apical or basal cochlea and compared them with acutely deafened (AD) rats of both sexes with normal hearing (NH) during development. We found that neonatal deafness significantly impacted the ITD sensitivity and the ITD tuning patterns restricted to apically driven IC neurons. In ND rats, the ITD sensitivity of apically driven neurons is reduced to values similar to basally driven neurons. The prevalence of ITD-sensitive apical neurons with a peak-shaped ITD tuning curve, which may reflect predominant input from the medial superior olivary (MSO) complex, in ND rats was diminished compared with that in AD rats (67%, AD vs 40%, ND). Conversely, monotonic-type responses rarely occurred in AD rats (14%) but were approximately equally as prevalent as peak-type tuning curves in ND rats (42%). Nevertheless, in ND rats, the ITD at the maximum slope of the ITD tuning curve was still more concentrated within the physiological ITD range in apically driven than in basally driven neurons. These results indicate that the development of high ITD sensitivity processed by low-frequency pathways depends on normal auditory experience and associated biases in ITD tuning strategies.

The Relationship Between Interaural Insertion-Depth Differences, Scalar Location, and Interaural Time-Difference Processing in Adult Bilateral Cochlear-Implant Listeners.

Sensitivity to interaural time differences (ITDs) in acoustic hearing involves comparison of interaurally frequency-matched inputs. Bilateral cochlear-implant arrays are, however, only approximately aligned in angular insertion depth and scalar location across the cochleae. Interaural place-of-stimulation mismatch therefore has the potential to impact binaural perception. ITD left-right discrimination thresholds were examined in 23 postlingually-deafened adult bilateral cochlear-implant listeners, using low-rate constant-amplitude pulse trains presented via direct stimulation to single electrodes in each ear. Angular insertion depth and scalar location measured from computed-tomography (CT) scans were used to quantify interaural mismatch, and their association with binaural performance was assessed. Number-matched electrodes displayed a median interaural insertion-depth mismatch of 18° and generally yielded best or near-best ITD discrimination thresholds. Two listeners whose discrimination thresholds did not show this pattern were confirmed via CT to have atypical array placement. Listeners with more number-matched electrode pairs located in the scala tympani displayed better thresholds than listeners with fewer such pairs. ITD tuning curves as a function of interaural electrode separation were broad; bandwidths at twice the threshold minimum averaged 10.5 electrodes (equivalent to 5.9 mm for a Cochlear-brand pre-curved array). Larger angular insertion-depth differences were associated with wider bandwidths. Wide ITD tuning curve bandwidths appear to be a product of both monopolar stimulation and angular insertion-depth mismatch. Cases of good ITD sensitivity with very wide bandwidths suggest that precise matching of insertion depth is not critical for discrimination thresholds. Further prioritizing scala tympani location at implantation should, however, benefit ITD sensitivity.

Effects of place of stimulation on the interaural time difference sensitivity in bilateral electrical intracochlear stimulations: Neurophysiological study in a rat model.

We examined the sensitivity of the neurons in the inferior colliculus (IC) in male and female rats to the interaural time differences (ITDs) conveyed in electrical pulse trains. Using bipolar pairs of electrodes that selectively activate the auditory nerve fibers at different intracochlear locations, we assessed whether the responses to electrical stimulation with ITDs in different frequency regions were processed differently. Most well-isolated single units responded to the electrical stimulation in only one of the apical or basal cochlear regions, and they were classified as either apical or basal units. Regardless of the cochlear stimulating location, more than 70% of both apical and basal units were sensitive to ITDs of electrical stimulation. However, the pulse rate dependence of neural ITD sensitivity differed significantly depending on the location of the stimulation. Moreover, ITD discrimination thresholds and the relative incidence of ITD tuning type markedly differed between units activated by apical and basal stimulations. With apical stimulation, IC neurons had a higher incidence of peak-type ITD function, which mostly exhibited the steepest position of the tuning curve within the rat's physiological ITD range of ±160μs and, accordingly, had better ITD discrimination thresholds than those with basal stimulation. These results support the idea that ITD processing in the IC might be determined by functionally segregated frequency-specific pathways from the cochlea to the auditory midbrain.

Interaural time difference tuning in the rat inferior colliculus is predictive of behavioral sensitivity

While a large body of literature has examined the encoding of binaural spatial cues in the auditory midbrain, studies that ask how quantitative measures of spatial tuning in midbrain neurons compare with an animal's psychoacoustic performance remain rare. Researchers have tried to explain deficits in spatial hearing in certain patient groups, such as binaural cochlear implant users, in terms of declines in apparent reductions in spatial tuning of midbrain neurons of animal models. However, the quality of spatial tuning can be quantified in many different ways, and in the absence of evidence that a given neural tuning measure correlates with psychoacoustic performance, the interpretation of such finding remains very tentative. Here, we characterize ITD tuning in the rat inferior colliculus (IC) to acoustic pulse train stimuli with varying envelopes and at varying rates, and explore whether quality of tuning correlates behavioral performance. We quantified both mutual information (MI) and neural d' as measures of ITD sensitivity. Neural d' values paralleled behavioral ones, declining with increasing click rates or when envelopes changed from rectangular to Hanning windows, and they correlated much better with behavioral performance than MI. Meanwhile, MI values were larger in an older, more experienced cohort of animals than in naive animals, but neural d' did not differ between cohorts. However, the results obtained with neural d' and MI were highly correlated when ITD values were coded simply as left or right ear leading, rather than specific ITD values. Thus, neural measures of lateralization ability (e.g. d' or left/right MI) appear to be highly predictive of psychoacoustic performance in a two-alternative forced choice task.

Sensitivity to interaural time differences in the inferior colliculus of cochlear implanted rats with or without hearing experience

For deaf patients cochlear implants (CIs) can restore substantial amounts of functional hearing. However, binaural hearing, and in particular, the perception of interaural time differences (ITDs) with current CIs has been found to be notoriously poor, especially in the event of early hearing loss. One popular hypothesis for these deficits posits that a lack of early binaural experience may be a principal cause of poor ITD perception in pre-lingually deaf CI patients. This is supported by previous electrophysiological studies done in neonatally deafened, bilateral CI-stimulated animals showing reduced ITD sensitivity. However, we have recently demonstrated that neonatally deafened CI rats can quickly learn to discriminate microsecond ITDs under optimized stimulation conditions which suggests that the inability of human CI users to make use of ITDs is not due to lack of binaural hearing experience during development. In the study presented here, we characterized ITD sensitivity and tuning of inferior colliculus neurons under bilateral CI stimulation of neonatally deafened and hearing experienced rats. The hearing experienced rats were not deafened prior to implantation. Both cohorts were implanted bilaterally between postnatal days 64-77 and recorded immediately following surgery. Both groups showed comparably large proportions of ITD sensitive multi-units in the inferior colliculus (Deaf: 84.8%, Hearing: 82.5%), and the strength of ITD tuning, quantified as mutual information between response and stimulus ITD, was independent of hearing experience. However, the shapes of tuning curves differed substantially between both groups. We observed four main clusters of tuning curves – trough, contralateral, central, and ipsilateral tuning. Interestingly, over 90% of multi-units for hearing experienced rats showed predominantly contralateral tuning, whereas as many as 50% of multi-units in neonatally deafened rats were centrally tuned. However, when we computed neural d’ scores to predict likely limits on performance in sound lateralization tasks, we did not find that these differences in tuning shapes predicted worse psychoacoustic performance for the neonatally deafened animals. We conclude that, at least in rats, substantial amounts of highly precise, “innate” ITD sensitivity can be found even after profound hearing loss throughout infancy. However, ITD tuning curve shapes appear to be strongly influenced by auditory experience although substantial lateralization encoding is present even in its absence.

Natural ITD statistics predict human auditory spatial perception.

A neural code adapted to the statistical structure of sensory cues may optimize perception. We investigated whether interaural time difference (ITD) statistics inherent in natural acoustic scenes are parameters determining spatial discriminability. The natural ITD rate of change across azimuth (ITDrc) and ITD variability over time (ITDv) were combined in a Fisher information statistic to assess the amount of azimuthal information conveyed by this sensory cue. We hypothesized that natural ITD statistics underlie the neural code for ITD and thus influence spatial perception. To test this hypothesis, sounds with invariant statistics were presented to measure human spatial discriminability and spatial novelty detection. Human auditory spatial perception showed correlation with natural ITD statistics, supporting our hypothesis. Further analysis showed that these results are consistent with classic models of ITD coding and can explain the ITD tuning distribution observed in the mammalian brainstem.

Deep learning of the binaural masking level difference

The binaural masking level difference (BMLD) is the improvement in the detection of a signal in noise observed for different interaural configurations. Durlach [J. Acoust. Sci. Am. 1206–1218 (1963)] derived equations that accurately predict much of the human BMLD psychophysical data. We trained a deep neural network to predict BMLDs, as calculated with Durlach's equations, based on waveforms of a 500 Hz signal in a white noise each presented from different locations. Crucially, the network was constrained via nodes configured to embody informative representations (Iten etal., 2018; arXiv:1807.10300). The deep neural network accurately predicted BMLDs for stimuli within a simulated azimuth and for stimuli with interaural time differences (ITDs) outside the range of a human head. Further, even though the model was not designed to imitate neural biophysics, we discovered that the dynamics of latent nodes bore similarities with published data on neural ITD tuning and rate-level responses to BMLD stimuli. The work demonstrates how advances in deep learning can be used to consolidate theoretical and experimental approaches to binaural detection.

The barn owls' Minimum Audible Angle.

Interaural time differences (ITD) and interaural level differences (ILD) are physical cues that enable the auditory system to pinpoint the position of a sound source in space. This ability is crucial for animal communication and predator-prey interactions. The barn owl has evolved an exceptional sense of hearing and shows abilities of sound localisation that outperform most other species. So far, behavioural studies in the barn owl often used reflexive responses to investigate aspects of sound localisation. Furthermore, they predominately probed the higher frequencies of the owl’s hearing range (> 3 kHz). In the present study we used a Go/NoGo paradigm to measure the barn owl’s behavioural sound localisation acuity (expressed as the Minimum Audible Angle, MAA) as a function of stimulus type (narrow-band noise centred at 500, 1000, 2000, 4000 and 8000 Hz, and broad-band noise) and sound source position. We found significant effects of both stimulus type and sound source position on the barn owls’ MAA. The MAA improved with increasing stimulus frequency, from 14° at 500 Hz to 6° at 8000 Hz. The smallest MAA of 4° was found for broadband noise stimuli. Comparing different sound source positions revealed smaller MAAs for frontal compared to lateral stimulus presentation, irrespective of stimulus type. These results are consistent with both the known variations in physical ITDs and variation in the width of neural ITD tuning curves with azimuth and frequency. Physical and neural characteristics combine to result in better spatial acuity for frontal compared to lateral sounds and reduced localisation acuity at lower frequencies.

Does electrode placement affect the interaural-time-difference acuity in bilateral cochlear-implant listeners?

Postlingually deafened bilateral cochlear-implant (CI) listeners can show limited interaural-time-difference (ITD) sensitivity, even when tested using highly controlled time-synchronized research processors. It is assumed that ITD discrimination requires interaural frequency-matched inputs. However, current bilateral CI programming procedures do not account for potential interaural place-of-stimulation mismatch. This study investigated the magnitude of interaural place-of-stimulation mismatch and its effects on ITD sensitivity in bilateral CI listeners. Ten bilateral CI listeners were tested on a two-interval left-right ITD discrimination task. Loudness balanced, 300-ms, 100 or 200 pulse-per-second, constant-amplitude, monopolar pulse trains were delivered to single-electrode pairs using time-synchronized research processors. ITD just noticeable differences (JNDs) were measured for five reference electrodes evenly distributed along the array in one ear, and for at least five comparison electrodes, generating ITD tuning curves. The interaural mismatch was estimated using both the ITD tuning curves and differences in the angular insertion depth from computed-tomography (CT) scans. Data showed that ITD tuning curves were relatively broad when compared to the amount of physical interaural place-of-stimulation mismatch from the CT scans. This suggests that most bilateral CI listeners do not experience appreciably reduced binaural sensitivity due to differences in electrode placement.

Extraction of Inter-Aural Time Differences Using a Spiking Neuron Network Model of the Medial Superior Olive.

The mammalian auditory system is able to extract temporal and spectral features from sound signals at the two ears. One important cue for localization of low-frequency sound sources in the horizontal plane are inter-aural time differences (ITDs) which are first analyzed in the medial superior olive (MSO) in the brainstem. Neural recordings of ITD tuning curves at various stages along the auditory pathway suggest that ITDs in the mammalian brainstem are not represented in form of a Jeffress-type place code. An alternative is the hemispheric opponent-channel code, according to which ITDs are encoded as the difference in the responses of the MSO nuclei in the two hemispheres. In this study, we present a physiologically-plausible, spiking neuron network model of the mammalian MSO circuit and apply two different methods of extracting ITDs from arbitrary sound signals. The network model is driven by a functional model of the auditory periphery and physiological models of the cochlear nucleus and the MSO. Using a linear opponent-channel decoder, we show that the network is able to detect changes in ITD with a precision down to 10 μs and that the sensitivity of the decoder depends on the slope of the ITD-rate functions. A second approach uses an artificial neuronal network to predict ITDs directly from the spiking output of the MSO and ANF model. Using this predictor, we show that the MSO-network is able to reliably encode static and time-dependent ITDs over a large frequency range, also for complex signals like speech.

Comparisons of electric and acoustic ITD coding in normal hearing gerbils

Small differences in the arrival time of sound between the two ears [interaural time differences (ITDs)] provide important cues for directional hearing and speech understanding in noise. Deaf subjects with bilateral cochlear implants (CIs) show relatively poor sensitivity to ITDs. It is unclear whether these limitations are due to differences in binaural brain circuits activated by electric compared to acoustic stimulation, mismatches in electric activation site across ears, or deafness-induced degradations in neural ITD processing. To identify potential limitations of electric ITD coding, we compared electric and acoustic ITD coding (i.e., ITD tuning and discrimination thresholds) in the same population of auditory brainstem and midbrain neurons in normal hearing gerbils. When compared in the same neurons, ITD coding to acoustic stimulation did not predict coding to electric stimulation. However, on a population level, neurons demonstrated surprising similarities in acoustic and electric ITD processing. ...

A Test of the Stereausis Hypothesis for Sound Localization in Mammals.

The relative arrival times of sounds at both ears constitute an important cue for localization of low-frequency sounds in the horizontal plane. The binaural neurons of the medial superior olive (MSO) act as coincidence detectors that fire when inputs from both ears arrive near simultaneously. Each principal neuron in the MSO is tuned to its own best interaural time difference (ITD), indicating the presence of an internal delay, a difference in the travel times from either ear to the MSO. According to the stereausis hypothesis, differences in wave propagation along the cochlea could provide the delays necessary for coincidence detection if the ipsilateral and contralateral inputs originated from different cochlear positions, with different frequency tuning. We therefore investigated the relation between interaural mismatches in frequency tuning and ITD tuning during in vivo loose-patch (juxtacellular) recordings from principal neurons of the MSO of anesthetized female gerbils. Cochlear delays can be bypassed by directly stimulating the auditory nerve; in agreement with the stereausis hypothesis, tuning for timing differences during bilateral electrical stimulation of the round windows differed markedly from ITD tuning in the same cells. Moreover, some neurons showed a frequency tuning mismatch that was sufficiently large to have a potential impact on ITD tuning. However, we did not find a correlation between frequency tuning mismatches and best ITDs. Our data thus suggest that axonal delays dominate ITD tuning.SIGNIFICANCE STATEMENT Neurons in the medial superior olive (MSO) play a unique role in sound localization because of their ability to compare the relative arrival time of low-frequency sounds at both ears. They fire maximally when the difference in sound arrival time exactly compensates for the internal delay: the difference in travel time from either ear to the MSO neuron. We tested whether differences in cochlear delay systematically contribute to the total travel time by comparing for individual MSO neurons the best difference in arrival times, as predicted from the frequency tuning for either ear, and the actual best difference. No systematic relation was observed, emphasizing the dominant contribution of axonal delays to the internal delay.

Neural Coding of Interaural Time Differences with Bilateral Cochlear Implants in Unanesthetized Rabbits.

Although bilateral cochlear implants (CIs) provide improvements in sound localization and speech perception in noise over unilateral CIs, bilateral CI users' sensitivity to interaural time differences (ITDs) is still poorer than normal. In particular, ITD sensitivity of most CI users degrades with increasing stimulation rate and is lacking at the high carrier pulse rates used in CI processors to deliver speech information. To gain a better understanding of the neural basis for this degradation, we characterized ITD tuning of single neurons in the inferior colliculus (IC) for pulse train stimuli in an unanesthetized rabbit model of bilateral CIs. Approximately 73% of IC neurons showed significant ITD sensitivity in their overall firing rates. On average, ITD sensitivity was best for pulse rates near 80-160 pulses per second (pps) and degraded for both lower and higher pulse rates. The degradation in ITD sensitivity at low pulse rates was caused by strong, unsynchronized background activity that masked stimulus-driven responses in many neurons. Selecting synchronized responses by temporal windowing revealed ITD sensitivity in these neurons. With temporal windowing, both the fraction of ITD-sensitive neurons and the degree of ITD sensitivity decreased monotonically with increasing pulse rate. To compare neural ITD sensitivity to human performance in ITD discrimination, neural just-noticeable differences (JNDs) in ITD were computed using signal detection theory. Using temporal windowing at lower pulse rates, and overall firing rate at higher pulse rates, neural ITD JNDs were within the range of perceptual JNDs in human CI users over a wide range of pulse rates. Many profoundly deaf people wearing cochlear implants (CIs) still face challenges in everyday situations, such as understanding conversations in noise. Even with CIs in both ears, they have difficulty making full use of subtle differences in the sounds reaching the two ears [interaural time difference (ITD)] to identify where the sound is coming from. This problem is especially acute at the high stimulation rates used in clinical CI processors. This study provides a better understanding of ITD processing with bilateral CIs and shows a parallel between human performance in ITD discrimination and neural responses in the auditory midbrain. The present study is the first report on binaural properties of auditory neurons with CIs in unanesthetized animals.

Emergence of ITD tuning in the MSO with a realistic periphery model

To localize sounds in the environment, animals mostly rely on spectro-temporal cues originating from the physical disparities of the sound waveforms impacting the two ears. Among those, the Interaural Time Difference (ITD) has been shown to be crucial in mammals for locating low-frequency sounds, and is known to be processed by neurons in a particular structure, the Medial Superior Olive (MSO). While it is classically considered that the emergence of ITD selectivity in a neuron of the MSO is simply due to differences in the axonal delays originating from the two ears and impinging those neurons (the so called delay-line model [1]), experimental evidence shows that the best delay (the ITD at which the neuron's firing rate is maximum) is also dependent on the frequency of the sound [2]. To investigate more on this challenging experimental observation, we developed a realistic periphery model to mimic cochlear inputs from auditory nerves fibers onto the MSO. Using known plasticity rules such as Spike Timing Dependent Plasticity to structure the wiring from those connections onto the MSO, we extend the work that has already been performed [3], and study the emergence of binaural tuning in the MSO in a realistic scenario. The system is trained with binaural sounds such as white noise, and then, as in most experimental papers, we tested the ITD selectivity of cells in the MSO by presenting pure tones at various frequencies. Finally, we discuss, from a coding point of view the potential implications raised by the frequency dependence of the best delay. As pointed out by recent work [4], with such a frequency-dependent best delay, neurons in the MSO should be seen as coding for a particular position in space, rather than for just a fixed delay difference.

Estimating characteristic phase and delay from broadband interaural time difference tuning curves.

Characteristic delay and characteristic phase are shape parameters of interaural time difference tuning curves. The standard procedure for the estimation of these parameters is based on the measurement of delay curves measured for tonal stimuli with varying frequencies. Common to all procedures is the detection of a linear behavior of the phase spectrum. Hence a reliable estimate can only be expected if sufficiently many relevant frequencies are tested. Thus, the estimation precision depends on the given bandwidth. Based on a linear model, we develop and implement methods for the estimation of characteristic phase and delay from a single broadband tuning curve. We present two different estimation algorithms, one based on a Fourier-analytic interpretation of characteristic delay and phase, and the other based on mean square error minimization. Estimation precision and robustness of the algorithms are tested on artificially generated data with predetermined characteristic delay and phase values, and on sample data from electrophysiological measurements in birds and in mammals. Increasing the signal-to-noise ratio or the bandwidth increases the estimation accuracy of the algorithms. Frequency band location and strong rectification also affect the estimation accuracy. For realistic bandwidths and signal-to-noise ratios, the minimization algorithm reliably and robustly estimates characteristic delay and phase and is superior to the Fourier-analytic method. Bandwidth-dependent significance thresholds allow to assess whether the estimated characteristic delay and phase values are meaningful shape parameters of a measured tuning curve. These thresholds also indicate the sampling rates needed to obtain reliable estimates from interaural time difference tuning curves.

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.

On the localization of complex sounds: temporal encoding based on input-slope coincidence detection of envelopes.

Behavioral and neural findings demonstrate that animals can locate low-frequency sounds along the azimuth by detecting microsecond interaural time differences (ITDs). Information about ITDs is also available in the amplitude modulations (i.e., envelope) of high-frequency sounds. Since medial superior olivary (MSO) neurons encode low-frequency ITDs, we asked whether they employ a similar mechanism to process envelope ITDs with high-frequency carriers, and the effectiveness of this mechanism compared with the process of low-frequency sound. We developed a novel hybrid in vitro dynamic-clamp approach, which enabled us to mimic synaptic input to brain-slice neurons in response to virtual sound and to create conditions that cannot be achieved naturally but are useful for testing our hypotheses. For each simulated ear, a virtual sound, computer generated, was used as input to a computational auditory-nerve model. Model spike times were converted into synaptic input for MSO neurons, and ITD tuning curves were derived for several virtual-sound conditions: low-frequency pure tones, high-frequency tones modulated with two types of envelope, and speech sequences. Computational models were used to verify the physiological findings and explain the biophysical mechanism underlying the observed ITD coding. Both recordings and simulations indicate that MSO neurons are sensitive to ITDs carried by spectrotemporally complex virtual sounds, including speech tokens. Our findings strongly suggest that MSO neurons can encode ITDs across a broad-frequency spectrum using an input-slope-based coincidence-detection mechanism. Our data also provide an explanation at the cellular level for human localization performance involving high-frequency sound described by previous investigators.

A neural measure of interaural correlation based on variance in spike count

Interaural Correlation (IAC) is related to variance in Interaural Time Difference (ITD) and Interaural Level Difference (ILD). While normalized IAC can account for behavioral performance in discrimination tasks, so can models directly employing this variance as a cue. Attempts at identifying a neural correlate of IAC discrimination have focused on changes in mean spike count, typically at the peaks of ITD tuning curves. We propose that IAC discrimination relies on variance in spike rates on the slope of neural tuning curves (for ITD). We developed a physiologically based hemispheric-balance model of IAC, where fluctuations in the ratio of activity between left- and right-brain serve as the detection cue to a reduction in IAC from unity, a ratio that is stimulus power invariant. Adjusting model parameters, we find that two orders of magnitude less activity is required in the variance-based, compared with mean spike-rate based, model, in order to achieve the same performance. This adjustment also revealed a necessary neural time integration of 10 ms, which is comparable with physiological estimates. The model was tested by recording neural responses from the midbrain of anesthetized guinea pigs to noise stimuli of various IAC.

Directional Hearing by Linear Summation of Binaural Inputs at the Medial Superior Olive

Neurons in the medial superior olive (MSO) enable sound localization by their remarkable sensitivity to submillisecond interaural time differences (ITDs). Each MSO neuron has its own "best ITD" to which it responds optimally. A difference in physical path length of the excitatory inputs from both ears cannot fully account for the ITD tuning of MSO neurons. As a result, it is still debated how these inputs interact and whether the segregation of inputs to opposite dendrites, well-timed synaptic inhibition, or asymmetries in synaptic potentials or cellular morphology further optimize coincidence detection or ITD tuning. Using in vivo whole-cell and juxtacellular recordings, we show here that ITD tuning of MSO neurons is determined by the timing of their excitatory inputs. The inputs from both ears sum linearly, whereas spike probability depends nonlinearly on the size of synaptic inputs. This simple coincidence detection scheme thus makes accurate sound localization possible.

GABAB receptors sharpen tuning of a sound localization circuit

Neurons in the medial superior olive (MSO) perform one of the most time sensitive computations in the brain. Situated in the mammalian brainstem just one synapse removed from the auditory nerve, MSO neurons encode the location of low-frequency sounds in the horizontal plane by detecting the simultaneous arrival times of auditory inputs driven from the two ears, a process termed ‘binaural coincidence detection’. Given that sounds travel at ∼34 cm ms−1, the physiologically relevant range of interaural time differences (ITDs) is sub-millisecond for humans and smaller animals. Consequently, the reliable encoding of ITDs requires extraordinary temporal precision that must be maintained at sound frequencies approaching ∼2 kHz, the limit of phase locking exhibited by excitatory inputs to the MSO in most mammals. At first glance, a sensory system so heavily dependent on temporal precision would seem a poor candidate for neuromodulation, especially neuromodulation of presynaptic release. Yet a study in this issue of The Journal of Physiology provides compelling evidence that presynaptic GABAB receptors modulate neurotransmitter release at synapses onto MSO neurons and that such modulation improves the resolution of binaural coincidence detection (Fischl et al. 2012). GABAB receptors are G-protein-coupled receptors that, when expressed presynaptically, act through a variety of potential mechanisms to inhibit release probability. How might this contribute to ITD detection? An important clue comes from an insightful study by Brenowitz et al. (1998), who asked how GABAB activation affects the reliability of high-frequency synaptic transmission. Recording from neurons in the chick nucleus magnocellularis, avian analogs of the input neurons to the mammalian MSO, the authors stimulated auditory nerve afferents to evoke trains of EPSCs. They observed that while GABAB receptor activation reduced EPSC amplitudes generally, at frequencies above 100 Hz short-term depression was dramatically reduced, rendering later EPSC amplitudes greater than un-modulated controls. Thus, the strength and reliability of high-frequency synaptic transmission was improved, presumably by preserving vesicles for later release. A subsequent study by Kuba et al. (2002) in the avian equivalent of the MSO showed that artificial reductions in release probability could sharpen ITD detection by narrowing the time window for suprathreshold summation of bilateral EPSPs. Do such mechanisms reside in mammalian MSO?Hassfurth et al. (2010) found functional and anatomical evidence that excitatory and inhibitory inputs express GABAB receptors in MSO neurons. This expression appeared to be developmentally regulated for excitatory inputs, as GABAB-mediated depression of EPSC amplitudes dropped to smaller, but still significant, levels in the 3 weeks following the onset of hearing at around postnatal day 12. In contrast, GABAB-mediated depression of IPSC amplitudes remained consistent across development. In this issue, Fischl and colleagues provide an elegant examination of the functional implications of GABAB receptor modulation in the MSO (Fischl et al. 2012). Recording from MSO neurons in slices, they confirmed the earlier finding that activation of GABAB receptors depresses individual EPSCs and IPSCs. In contrast to the Hassfurth study, they found that IPSC decay kinetics were slowed by GABAB activation at mature ages and that EPSC depression remained strong across development. Next, in a result reminiscent of the Brenowitz findings, the authors demonstrated that GABAB activation reduced the amount of depression within 50–200 Hz trains of PSCs, yielding trains with more stable amplitudes. Fischl and colleagues then simulated binaural ITDs in the slice using trains of bilateral synaptic stimuli to evoke EPSPs. The firing of MSO neurons was highly sensitive to these simulated ITDs. Upon addition of the GABAB agonist baclofen to the bath, ITD functions narrowed significantly. Conversely, when a GABAB antagonist was added, ITD functions widened. This latter result provides important confirmation that GABA can be released under physiological conditions (albeit in a brain slice), and even more importantly, GABA can achieve concentrations sufficient to modulate ITD detection. As conventional stimulation techniques do not permit separate stimulation of excitatory and inhibitory inputs to the MSO, ionotropic inhibitory receptors were blocked in these experiments. To circumvent this, the authors developed a model incorporating excitatory and inhibitory inputs driven by in vivo-like patterns. Simulations revealed that both the amplitude modulation of EPSCs and IPSCs and the kinetic slowing of IPSCs by GABAB modulation significantly sharpened ITD tuning in MSO neurons. Moreover, this sharpening persisted over a range of simulated sound intensities. Together, these results provide compelling evidence that GABAB receptors on presynaptic terminals in the MSO afford a mechanism for rapidly and reversibly sharpening the receptive fields of MSO neurons. When this mechanism comes into play is an exciting question for future studies. At present, the source of GABAergic input to the post-hearing MSO remains a mystery (the primary inhibitory inputs to MSO are glycinergic), but two likely possibilities present themselves. GABA release from an auditory source might be linked to sound intensity levels and provide a way to dynamically dampen highly active synapses. Alternatively, GABAergic inputs from a non-auditory centre might link receptive field modulation with attention or other behavioural states, possibly enabling the system to select between detecting weak auditory stimuli and precisely localizing strong ones. Getting to the bottom of this will probably require a combination of careful anatomy and electrophysiology. More broadly, the present results highlight the growing evidence that computations in the auditory brainstem are subject to modulation (e.g. Kotak et al. 2001; Magnusson et al. 2008). Given the highly dynamic nature of auditory stimuli, this is perhaps not as surprising as it once seemed. It does hint, however, that a rich repertoire of modulatory mechanisms awaits discovery.