A Physiologically-Based Population Rate Code for Interaural Time Differences (ITDs) Predicts Bandwidth-Dependent Lateralization

1. Interaural level differences (ILDs), created by the head and pinna, have long been known to be the dominant acoustic cue for azimuthal localization of high-frequency tones. However, psychophysical experiments have demonstrated that human subjects can also lateralize complex high-frequency sounds on the basis of interaural time differences (ITDs) of the signal envelope. The lateral superior olive (LSO) is one of two pairs of binaural nuclei where the primary extraction of binaural cues for sound source location occurs. "IE" cells in LSO are inhibited by stimuli to the contralateral and excited by stimuli to the ipsilateral ear, and their response rate is therefore dependent on ILD. Anatomic specializations in the afferent pathways to the LSO suggest that this circuit also has a function in the detection of timing cues. We hypothesized that, besides ILD sensitivity, the IE property also conveys a sensitivity to ITDs of amplitude-modulated (AM) tones and could provide the physiological substrate for the psychophysical effect mentioned above. 2. In extracellular recordings from binaural LSO cells in barbiturate-anesthetized cats, response rate was a periodic function of ITDs of AM stimuli, i.e., all cells displayed ITD sensitivity. Binaural responses were smaller than responses to stimulation of the ipsilateral ear alone and were minimal when the envelopes in both ears were in-phase or nearly so. There was good correspondence between responses to ITDs and to dynamic interaural phase differences (IPDs), created by a difference in the envelope frequency to the two ears. Qualitatively, the responses were consistent with the outcome of an IE operation on temporally structured inputs. 3. To compare the relative importance of ILD and ITD, responses to combinations of the two cues were obtained. Despite robust ITD sensitivity in all binaural LSO cells encountered, the changes in response rate that would occur in response to naturally occurring ITDs were small in comparison with the changes expected for naturally occurring ILDs. The main limitation on ITD sensitivity was a steep decline in average discharge rate as the modulation frequency exceeded several hundred Hertz. 4. ITD sensitivity was also present to broadband stimuli, again with minimal rates occurring near 0 ITD. The sensitivity depended in a predictable fashion on the passband of filtered noise and was absent to binaurally uncorrelated noise bands. In response to clicks, ILDs interacted with ITD in a complicated fashion involving amplitude and latency effects. 5. Three low-characteristic frequency (CF) LSO cells were encountered that were IE and showed ITD sensitivity to the fine structure of low-frequency stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

We assessed neural sensitivity to interaural time differences (ITDs) conveyed in the temporal fine structure (TFS) of low-frequency sounds and ITDs conveyed in the temporal envelope of amplitude-modulated (AM'ed) high-frequency sounds. Using electroencephalography (EEG), we recorded brain activity to sounds in which the interaural phase difference (IPD) of the TFS (or the modulated temporal envelope) was repeatedly switched between leading in one ear or the other. When the amplitude of the tones is modulated equally in the two ears at 41 Hz, the interaural phase modulation (IPM) evokes an IPM following-response (IPM-FR) in the EEG signal. For low-frequency signals, IPM-FRs were reliably obtained, and largest for an IPM rate of 6.8 Hz and when IPD switches (around 0°) were in the range 45-90°. IPDs conveyed in envelope of high-frequency tones also generated IPM-FRs; response maxima occurred for IPDs switched between 0° and 180° IPD. This is consistent with the interpretation that distinct binaural mechanisms generate the IPM-FR at low and high frequencies, and with the reported physiological responses of medial superior olive (MSO) and lateral superior olive (LSO) neurons in other mammals. Low-frequency binaural neurons in the MSO are considered maximally activated by IPDs in the range 45-90°, consistent with their reception of excitatory inputs from both ears. High-frequency neurons in the LSO receive excitatory and inhibitory input from the two ears receptively--as such maximum activity occurs when the sounds at the two ears are presented out of phase.

The auditory system uses three cues to decode sound location: interaural time differences (ITDs), interaural level differences (ILDs), and spectral notches (SNs). Initial processing of these cues is done in separate brainstem nuclei, with ITDs in the medial superior olive, ILDs in the lateral superior olive, and SNs in the dorsal cochlear nucleus. This work addresses the nature of the convergence of localization information in the central nucleus of the inferior colliculus (ICC). Ramachandran et al. (1999) argued that ICC neurons of types V, I, and O, respectively, receive their predominant inputs from ITD-, ILD-, and SN-sensitive brainstem nuclei, suggesting that these ICC response types should be differentially sensitive to localization cues. Here, single-unit responses to simultaneous manipulation of pairs of localization cues were recorded, and the mutual information between discharge rate and individual cues was quantified. Although rate responses to cue variation were generally consistent with those expected from the hypothesized anatomical connections, the differences in information were not as large as expected. Type I units provide the most information, especially about SNs in the physiologically useful range. Type I and O units provide information about ILDs, even at low frequencies at which actual ILDs are very small. ITD information is provided by a subset of all low-frequency neurons. Type V neurons provide information mainly about ITDs and the average binaural intensity. These results are the first to quantify the relative representation of cues in terms of information and suggest a variety of degrees of cue integration in the ICC.

Interaural time difference (ITD) detection plays a critical role in sound localization. Some neurophysiology experiments found that the ITD discrimination threshold for single neuron in medial superior olive (MSO) is about 20 μs. In order to reveal the ITD coding mechanism essentially, an ITD detection model has been proposed in this paper based on the anatomical structure of the mammalian auditory system. Most previous research only discuss the relationship between the ITDs and the spike rate of the MSO neuron. In these results, the spike rate difference is under 1 spike/s when the ITD changes in 20 μs. It means the neuron needs more than 1 s to distinguish the ITD by spike rate coding. This explanation contradicts with the rapid and accurate sound localization response in animal psychoacoustics experiments. In our study, the neural coding in ITD detection model has been investigated via the approach of circle maps and symbolic dynamics. With these two methods, the ITDs under 20 μs can be detected in 1 s. This neural coding hypothesis agrees with the ITD detection response time in the animal behavior experiments.

Sound localisation is defined as the ability to identify the position of a sound source. The brain employs two cues to achieve this functionality for the horizontal plane, interaural time difference (ITD) by means of neurons in the medial superior olive (MSO) and interaural intensity difference (IID) by neurons of the lateral superior olive (LSO), both located in the superior olivary complex of the auditory pathway. This paper presents spiking neuron architectures of the MSO and LSO. An implementation of the Jeffress model using spiking neurons is presented as a representation of the MSO, while a spiking neuron architecture showing how neurons of the medial nucleus of the trapezoid body interact with LSO neurons to determine the azimuthal angle is discussed. Experimental results to support this work are presented.

Sensitivity for interaural time and intensity difference of auditory midbrain neurons in the grassfrog

This study reports simulations of recent physiological results from the gerbil medial superior olive (MSO) that reveal that blocking glycinergic inhibition can shift the tuning for the interaural time difference (ITD) of the cell (Brand et al., 2002). Our simulations indicate that the model proposed in the study by Brand et al. (2002) requires precisely timed, short-duration inhibition with temporal accuracy exceeding that described in the auditory system. An alternative model is proposed that incorporates two anatomic observations in the MSO: (1) the axon arises from the dendrite that receives ipsilateral inputs; and (2) inhibitory synapses are located primarily on the soma in adult animals. When the inhibitory currents are activated or blocked, the model cell successfully simulates experimentally observed shifts in the best ITD. The asymmetrical cell structure allows an imbalance between the ipsilateral and contralateral excitatory inputs and shifts the ITD curve such that the best ITD is not at zero. Fine adjustment of the best ITD is achieved by the interplay of somatic sodium currents and synaptic inhibitory currents. The shift of the best ITD in the model is limited to approximately 0.2 ms, which is behaviorally significant with respect to ITDs encountered in perceptual tasks. The model suggests a mechanism for dynamically "fine-tuning" the ITD sensitivity of MSO cells by the opponency between depolarizing sodium currents and hyperpolarizing inhibitory currents.

Analytical description of coincidence detection synaptic mechanisms in the auditory pathway

The localization of low-frequency sounds (less than 3 kHz) along the azimuth involves comparing the ongoing difference in the time of arrival of a sound at the two ears. Information about interaural time differences (ITDs) is derived from an initial comparison performed in the superior olivary complex. However, little is known about which aspects of this information are transformed as it ascends the brainstem. To address this issue, we compared the ITD sensitivity of neurons in the inferior colliculus (IC) and auditory thalamus, successive stations in the auditory pathway. We found ITD sensitivity in the IC and thalamus to be similar in several respects. At both levels, the large majority of neurons responded maximally to ITDs within the range that a rabbit would normally encounter (+/- 300 microseconds) and preferred ipsilateral delays, delays that would be created by sounds in the contralateral sound field. The range of frequencies over which ITD sensitivity was expressed was also similar in the midbrain and thalamus. Several differences were also apparent. In comparison to IC neurons, neurons in the thalamus responded over more restricted ranges of ITD, responded at lower rates, and, in response to monaural stimulation, showed an increased influence of inhibition. Finally, a greater proportion of thalamic units had characteristic delays corresponding to intermediate discharge rates. The preservation of a bias for ipsilateral delays from IC to thalamus suggests that a representation of contralateral azimuths is present at both levels. Similarities between the two levels suggest that information about ITDs is faithfully transmitted from midbrain to thalamus. Differences in ITD sensitivity, such as the sharper tuning for ITDs, suggest that the thalamus is not a simple relay. Enhanced sensitivity to ITDs should translate to better-defined azimuthal receptive fields, and therefore may be a step toward achieving an optimal representation of azimuth within the auditory pathway.

Neuronal sensitivity to the interaural time difference of the sound envelope in the mouse inferior colliculus

We investigated the role of GABAergic inhibition on the responses of inferior colliculus (IC) neurons sensitive to interaural time differences (ITDs) in anesthetized guinea pigs. Responses to static and dynamic ITDs were obtained before, during, and after recovery from ionotophoretic application of GABA, or antagonists to the GABA(A) receptor gabazine and bicuculline. For most neurons, a linear relationship was observed between discharge rates evoked by a particular ITD during drug application and control discharge rates. Blocking GABAergic inhibition, or adding exogenous GABA, scaled IC discharge rates in a multiplicative (divisive) and/or additive (subtractive) manner. When the influence of iontophoresed GABA antagonists or exogenous GABA on discharge rates was accounted for, GABAergic inhibition was found to have no effect on the ITD tuning properties of IC neurons. The tuning sharpness of ITD functions, the ITD that evoked 50% response magnitude, and the relative symmetry of ITD functions around their peak response were unaffected by blockade of inhibition or addition of tonic inhibition. However, the ability of neurons to discriminate between ITDs by virtue of differences in their discharge rate was altered by blocking or adding GABA. We propose that inhibition in the IC is involved in the control of the neural gain of the output of IC neurons rather than the regulation of ITD tuning. This gain control appears to arise from a combination of additive and multiplicative processes, and may involve mechanisms such as shunting inhibition or changes in the efficacy of inhibitory and excitatory inputs.

Responses of a population model of low‐frequency inferior colliculus (IC) neurons to a pair of broadband clicks were evaluated. IC inputs came from Hodgkin‐Huxley models of medial superior olive (MSO) and cochlear nucleus bushy cells driven by a stochastic auditory nerve model. Each IC cell received converging inputs that were excitatory from ipsilateral MSO and inhibitory from contralateral MSO. Convergence of multiple excitatory, ipsilateral MSO inputs with similar interaural time difference (ITD) tuning improved ITD sensitivity and reduced the influence of MSO onset responses caused by monaural, rather than binaural, coincidences. Inhibition that lasted over several milliseconds suppressed IC responses to the lagging click. The effect of the inhibition depended on the ITD tuning of the excitation and inhibition converging on a given IC neuron. With appropriate convergence, the IC population showed no response to the lagging click at short delays, and responded to the lagging click but did not encode its ITD at intermediate delays. Only at longer inter‐click delays did IC responses show sensitivity to the lagging click ITD, consistent with the perceptual phenomenon of the precedence effect. [Work supported by NSF and NIH].

The binaural cue decoding in the human auditory pathway occurs in the medial superior olive (MSO) and the lateral superior olive (LSO). The MSO is sensitive to interaural time difference (ITD), whereas the LSO is sensitive to interaural level difference as well as to ITD at low frequencies. Functional models of such organs have been presented previously [Pulkki and Hirvonen, Acta Acoustica united with Acoustica 95, 883–900 (2009)]. However, the outputs of those models are not as such applicable as the level of the output varies for a point-like broadband stimulus depending on the frequency and between the models. Here, a method is presented to combine the outputs of such models and an additional model of the MSO designed to decode directional cues based on broadband envelope time-shifts between the ear canal signals. Applicable cues are obtained by mapping the outputs into azimuth direction values following the idea of self-calibration, and by favoring the cue values suggesting more lateral directions. Furthermore, it is shown how the resulting directional cues can be applied to form a binaural activity map, and that the activity map corresponds to the human perception in several scenarios of psychoacoustical experiments.

We are regularly exposed to several concurrent sounds, producing a mixture of binaural cues. The neuronal mechanisms underlying the localization of concurrent sounds are not well understood. The major binaural cues for localizing low-frequency sounds in the horizontal plane are interaural time differences (ITDs). Auditory brain stem neurons encode ITDs by firing maximally in response to "favorable" ITDs and weakly or not at all in response to "unfavorable" ITDs. We recorded from ITD-sensitive neurons in the dorsal nucleus of the lateral lemniscus (DNLL) while presenting pure tones at different ITDs embedded in noise. We found that increasing levels of concurrent white noise suppressed the maximal response rate to tones with favorable ITDs and slightly enhanced the response rate to tones with unfavorable ITDs. Nevertheless, most of the neurons maintained ITD sensitivity to tones even for noise intensities equal to that of the tone. Using concurrent noise with a spectral composition in which the neuron's excitatory frequencies are omitted reduced the maximal response similar to that obtained with concurrent white noise. This finding indicates that the decrease of the maximal rate is mediated by suppressive cross-frequency interactions, which we also observed during monaural stimulation with additional white noise. In contrast, the enhancement of the firing rate to tones at unfavorable ITD might be due to early binaural interactions (e.g., at the level of the superior olive). A simple simulation corroborates this interpretation. Taken together, these findings suggest that the spectral composition of a concurrent sound strongly influences the spatial processing of ITD-sensitive DNLL neurons.