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7 The Superior Olivary Complex Shigeyuki Kuwada and Tom C. T. Yin Learning Objectives n The reader will be able to describe the anatomic divisions of the superior olivary complex (SOC). n The reader will be able to describe the binaural cues and neural circuitry used by neurons in the SOC to localize sounds n The reader will be able to describe the anatomic pathways linking the SOC to the cochlear nuclei, lateral lemniscus, and inferior colliculus. n The reader will be able to describe the frequency bias of the medial superior olive and the lateral superior olive. Key Words. Superior olivary complex, lateral superior olive, medial superior olive, medial nucleus of the trapezoid body, periolivary nuclei, medial olivocochlear system, lateral olivocochlear system, interaural time differences, interaural intensity differences, sound localization Functional Anatomy of the Superior Olivary Complex The superior olivary complex (SOC) is an important relay center for ascending auditory information as it receives projections from the cochlear nucleus, which in turn is the destination of all auditory nerve fibers from the cochlea. Since both cochlear nuclei impinge upon cells in the SOC, it represents the initial site of binaural interaction. The SOC is so named because anatomically it is in a superior position relative to the inferior olivary complex. The term olivary is based on the olive-shaped protuberance on the ventral lateral surface of the medulla created by the underlying inferior olivary complex. The SOC extends from the rostral medulla to the caudal pons and is called a complex because it represents many nuclear groups. The SOC can be functionally divided into a feedback system to the cochlea (olivocochlear system), an inhibitory periolivary system and a sound-localization system. Anatomically, there is considerable overlap between these systems. The SOC varies in size and composition among species (Figure 7–1). The main nuclei, the lateral (LSO) and medial (MSO, Figure 7–1, green filled) superior olivary nuclei can usually be identified in most species, but the nuclei that surround the LSO and MSO, viz., the periolivary nuclei (Figure 7–1, gray filled), take many forms. The tuning of neurons in LSO is biased towards high frequencies, whereas those in the MSO are biased towards low frequencies (Guinan et al., 1972). Thus, the relative size of the LSO and MSO reflect the animal’s frequency range of hearing (Glendenning & Masterton, 1998). So, animals with a hearing bias towards high frequency sounds (e.g., mice and rats) have a large LSO and a small MSO. Animals with good low and high frequency hearing (e.g., cats) have a prominent LSO and MSO. Humans have a hearing bias towards low frequency sounds so the most prominent nucleus is the MSO. 161 162 Translational Perspectives in Auditory Neuroscience: Normal Aspects of Hearing (SPON) although they are not entirely equivalent in their inputs and outputs. The MNTB is classically considered a main nucleus but we include it with the periolivary group because it logically fits with this group. The trapezoid body (aka, ventral acoustic stria) is a thick band of axons bounded ventrally by the ventral border of the brainstem and the pyramidal tract and the approximate position of the dorsal border is shown in Figure 7–2B. The trapezoid body is primarily made up of axons of cochlear nucleus (CN) neurons projecting to the SOC, axons from SOC nuclei to other SOC nuclei, and axons from SOC nuclei projecting to higher structures. The trapezoid body is so named because the descending axons from the abducens (cranial nerve VI) nucleus create an image of a trapeze with the descending abducens nerve fibers being the ropes of the trapeze and the crossing axons the seat or body of the trapeze. Feedback System to the Cochlea (olivocochlear system) Figure 7–1. The superior olivary complex in different species. Lateral superior olive (LSO), medial superior olive (MSO), medial nucleus of the trapezoid body (MNTB). Based on Schwartz, 1992. Mouse and rat provided by Tetsufumi Ito. The LSO in humans is difficult to identify and even more difficult is the medial nucleus of the trapezoid body (MNTB), a periolivary nucleus that has strong projections to the LSO in most mammals (Bazwinsky et al., 2003). Figure 7–2 shows the organization of the SOC in the cat from its caudal (Figure 7–2A) to rostral (Figure 7–2D) extent. The main nuclei of the SOC, the MSO and LSO, are depicted as green and the periolivary nuclei as gray. The periolivary nuclei surround the main nuclei and are named according to position: medial (MNTB), ventral (VNTB), and lateral (LNTB) nuclei of the trapezoid body and the anterior lateral (ALPO), dorsal lateral (DLPO), and dorsal medial (DMPO) periolivary nuclei. In rodents the DMPO nucleus is called the superior paraolivary nucleus Our treatment of this system is brief because it will be comprehensively discussed by Guinan (see Chapter 11). This is a feedback system where neurons in the SOC project their axons to the hair cells of the cochlea, hence the name olivocochlear system. A major role of this system is to actively alter the mechanical tuning of the basilar membrane by affecting the motility of the outer hair cells (OHCs). This system is often referred to as a cochlear amplifier. Figure 7–2 shows the locations of olivocochlear neurons that were stained by injecting a retrograde tracer, into the left cochlea of a cat (Vetter et al., 1991; Warr et al., 2002). Two populations of neurons can be seen, those located medial and those located lateral to the MSO and are appropriately named the medial (MOC) and lateral (LOC) olivocochlear neurons. The LOC neurons can be further divided into those that are in close proximity to the margins of the LSO (marginal LOC) and those located more distally to the LSO (para-LOC). The olivocochlear neurons project bilaterally, however, MOC neurons project predominantly to the contralateral cochlea whereas those in the LOC project primarily to the ipsilateral cochlea. Figure 7–2. Transverse sections depicting the caudal (A) to rostral (D) extent of the SOC. Also depicted in the center is a line drawing of the whole brainstem at that level of the SOC. The main nuclei, medial superior olive (MSO) and lateral superior olive (LSO) are colored green. The periolivary nuclei, medial (MNTB), ventral (VNTB) and lateral (LNTB) nuclei of the trapezoid body and the anterior lateral (ALPO), dorsal lateral (DLPO), and dorsal medial (DMPO) periolivary nuclei are colored gray. Also shown at the rostral extreme is the ventral nucleus of the lateral lemniscus (VNLL). Adapted from Warr et al., 2002, with permission by the Association for Research in Otolaryngology. 163 164 Translational Perspectives in Auditory Neuroscience: Normal Aspects of Hearing Figure 7–3 provides a schematic of the olivocochlear system. The MOC neurons are myelinated and innervate the base of OHCs using acetylcholine as its transmitter (Vetter et al., 1991), although a small proportion may use GABA as a transmitter (Whitlon & Sobkowicz, 1989). About two-thirds of the neurons project to the contralateral cochlea and one-third to the ipsilateral cochlea. In the cat, the MOC neurons almost exclusively reside in three periolivary nuclei, VNTB, MNTB, and DMPO. These neurons show Figure 7–3. Schematic of olivocochlear system. medial olivocochlear (MOC), lateral olivocochlear (LOC), outer hair cell (OHC), inner hair cell (IHC), tectoral membrane (TH), pyramidal tract (PT). Adapted from Warr et al., 2002, with permission by the Association for Research in Otolaryngology. The Superior Olivary Complex sharp frequency tuning and project to many hair cells located above and below the frequency tuning of the MOC neuron (Liberman & Brown, 1986). The marginal cell region of the anteroventral cochlear nucleus (AVCN) project bilaterally to MOC neurons. It is hypothesized that the marginal cells provide information about sound intensity as part of a feedback gain control system comprising the cochlea, cochlear neurons, CN, MOC neurons, and cochlear OHCs (Ghoshal & Kim, 1997; Ye et al., 2000). The function of the LOC neurons is not well understood because their small size and unmyelinated axons make recordings difficult. In cat, cell bodies of LOC neurons are preferentially distributed in the low frequency region (lateral limb) of the LSO. They project to the inner hair cells (IHCs) where they synapse on the afferent terminals of auditory nerve fibers (Liberman, 1980). This projection appears tonotopic, because injections of anterograde tracers at progressively more medial regions of the LSO label terminals near IHCs at progressively more basal locations in the ipsilateral cochlea (Guinan et al., 1984). LOC neurons use acetylcholine as a transmitter, but other neuroactive substances (enkephalin, Altschuler et al., 1984); dynorphin, Abou-Madi et al., 1987); calicitonin gene-related peptide, Vetter et al., 1991) are found to colocalize with acetylcholine. The LOC neurons receive inputs from the ipsilateral, posteroventral cochlear nucleus (PVCN: Warr, 1982). Inhibitory, Periolivary System This system does not appear to have a unitary function and is, as a whole, the least understood group of nuclei of the SOC. A common feature is that most periolivary neurons are immunoreactive for glycine and GABA. Thus, these neurons provide inhibitory inputs to the CN (Figure 7–4) as well as to other nuclei of the SOC. In general, the role of inhibition in sensory systems is to sharpen receptive fields, enhance contrast and improve frequency tuning. Also shown in Figure 7–4 is the projection of MOC neurons to the contralateral VCN. As described (see Figures 7–2 and 7–3), these neurons use acetylcholine as a transmitter. The periolivary nuclei, except for the MNTB, show dense immunoreactive labeling for serotoninergic fibers (Figure 7–5). Serotonin is considered a neuromodulator and is produced in the Raphe nucleus, a structure that runs the length of the brainstem. Serotonin levels are low during sleep Figure 7–4. Outputs of periolivary nuclei to cochlear nuclei. Adapted from Helfert and Aschoff, 1997, with permission by the Oxford University Press, Inc. 165 166 Translational Perspectives in Auditory Neuroscience: Normal Aspects of Hearing and high during vigilant states. A local injection of serotonin usually usually depresses responses and increases neural response latencies to sound in neu- Figure 7–5. Distribution of immunoreactive serotonergic fibers in the SOC of the cat. Reprinted from (Thompson and Schofield, 2000), with permission by Microscopy Research Techniques (John Wiley & Sons). rons of the inferior colliculus, though the effect can be stimulus dependent (Hurley & Pollak, 1999). Another common feature is that the periolivary nuclei receive their excitatory input from the CN (Figure 7–6). These inputs are from specific cell types (octopus, globular bushy and stellate cells) in the VCN. The collateral branches in the schematic of Figure 7–6 are not necessarily meant to indicate that the same cell in the CN innervates different periolivary nuclei, though most cells do innervate more than one target, but instead that the same cell type can innervate more than one periolivary nucleus. The MNTB and VMPO receive inputs from the contralateral VCN, the DLPO, and LNTB from the ipsilateral VCN, and the DMPO and VNTB from both VCNs (see review by Helfert & Aschoff, 1997). In addition to the inputs to the SOC from the cochlear nuclei, higher-order structures also provide inputs to the SOC. Figure 7–7 shows these descending inputs. The heaviest projections are from the thalamus and inferior colliculus (IC), with a lighter projection from the auditory cortex (Thompson & Schofield, 2000). Interestingly, the DMPO and VNTB are the major recipients of these inputs and they are the only periolivary nuclei that receive input from both CN (see Figure 7–6). Figure 7–6. Cochlear nucleus inputs to periolivary nuclei. Adapted from Helfert and Aschoff, 1997, with permission by the Oxford University Press, Inc. The VNTB houses many MOC neurons and many of these neurons are excited by binaural sound stimulation, consistent with the inputs from both CN. MOC neurons exhibit a slow chopping firing pattern that persists for the duration of the sound (Liberman & Brown, 1986). In contrast, the predominant response of DMPO/SPON neurons is suppression to sound stimulation followed by a robust off-response when the sound is turned off (Kulesza et al., 2003; Kuwada & Batra, 1999). These neurons have a strong preference to sounds presented to the contralateral ear. As described above, DMPO/SPON neurons receive an excitatory input from octopus cell in the contralateral CN as well as a weak input from stellate cells in the ipsilateral CN. This structure also receives a strong projection from the ipsilateral MNTB that uses the inhibitory transmitter, glycine. So, the suppression seen to contralateral sound stimulation is most likely created by the MNTB input, and release from inhibition, that is, at sound offset, creates an off response through a rebound mechanism (Kuwada & Batra, 1999). Examples of off-responses recorded in or near the vicinity of the DMPO in the unanesthetized rabbit is shown Figure 7–7. Schematic of major descending projections to the SOC. Adapted from Thompson and Schofield (2000), with permission by Microscopy Research Techniques (John Wiley and Sons). The Superior Olivary Complex in Figure 7–8. Both of the neurons display suppression to a 50-msec tone burst at high and low sound levels, followed by a punctuate but long-lasting off response. The rate-level function of these two neurons (panels C & F) indicates that the off-response is monotonic over a wide intensity range (~60 to 70 dB). Humans are sensitive to even a wider range, but the range seen in these off neurons is 2 to 3 times greater than that seen in the auditory nerve. Although the response to tones is suppressive, periodic sinusoidal amplitude modulated (SAM) tone can entrain the off-response to create a time-locked response to the modulation frequency. Figure 7–9 (left column) shows the response of a SOC neuron in the form of Figure 7–8. Examples of SOC neurons that show an off response to tone bursts and their rate-level functions to the off response. Adapted from Kuwada and Batra (1999), with permission by the Society for Neuroscience via Copyright Clearance Center. 167 Figure 7–9. Response of an off-neuron to SAM tones. Left column: post-stimulus time histograms to modulation frequencies between 25 and 800 Hz. Right column: corresponding cycle histograms binned over a cycle of the modulation frequency. Carrier frequency = 6 kHz, intensity = 42 dB SPL. Adapted from Kuwada and Batra (1999), with permission by the Society for Neuroscience via Copyright Clearance Center. 168 poststimulus time histograms to different modulation frequencies. At 800 Hz, there is a weak sustained response during the 1100 msec SAM tone followed by a robust off-response. However, at progressively lower modulation frequencies, the sustained response becomes more robust and the off response at the lowest modulation frequencies (50 and 25 Hz) blends completely with the sustained response. The cycle histograms created by averaging the response over one cycle of the modulation frequency (right column) only over the stimulus duration indicate that the spike timing is highly locked to the modu- The Superior Olivary Complex lation frequency, even at the highest modulation frequency where the sustained response is weak. Careful analysis of the phase indicates that the sustained response is due to the entrainment of the neuron’s off response (Kuwada & Batra, 1999). As shown in Figure 7–9, this off response is present over a wide range of modulation frequencies, and is also responsive over a wide range of sound levels and modulation depths. An example is shown in Figure 7–10. When synchrony is measured, the modulation transfer function to sound intensity (Figure 7–10A) and to modulation depth (Figure 7–10C) both show primarily Figure 7–10. Modulation transfer functions (MTFs) of an off-neuron as a function of sound level and modulation depth. MTFs based on synchrony (A) and spike rate (B) at different sound levels. MTFs based on synchrony (C) and spike rate (D) at different modulation depths measured at 50 dB SPL. E. Synchrony as a function of level and modulation depth measured at 100 Hz modulation. F. Spike rate as a function of level and modulation depth measured at 100 Hz modulation. Adapted from Kuwada and Batra (1999), with permission by the Society for Neuroscience via Copyright Clearance Center. 169 170 Translational Perspectives in Auditory Neuroscience: Normal Aspects of Hearing a low-pass shape. When measured as a function of intensity or modulation depth (at 100 Hz modulation) synchrony becomes asymptotic (Figure 7–10E). In contrast, the spike rate modulation transfer functions to intensity and depth is primarily band pass in shape. The spike rate is non-monotonic with sound level and monotonic with modulation depth (Figure 7–10F). A common view of the role of inhibition is that it attenuates or suppresses post-synaptic neural activity. Although this is true for off neurons, the robust discharge when inhibition is released adds a new dimension. For simple sounds, (e.g., tones), the off response can code a wide range of sound levels (see Figure 7–8). For complex sounds, the off response becomes entrained to each modulation, resulting in precise temporal coding of the envelope (see Figures 7–9 and 7–10) Off responses in the SOC of rats are almost exclusively found in the SPON (Kulesza et al., 2003). Unlike the robust off response seen in the unanesthetized rabbit (e.g., see Figure 7–8), the off responses in the anesthetized rat often constitutes a single action potential. Neurons in the DMPO and SPON project to the ipsilateral IC using GABA as a transmitter (Saldana & Berrebi, 2000). The role of this projection is unclear but would serve to modulate AM sensitivity or be a source of AM processing in the midbrain. Kadner and Berrebi (2008) have suggested that off neurons may play a role in gap detection. Question 1 Are there diseases known to result in disordered processing in the human SOC? Answer 1 Diseases like multiple sclerosis do target myelinated fibers and the SOC receives inputs from large myelinated axons. However, this disease has wide spread effects and would not specifically target the SOC. Vascular strokes in this area of the brainstem are often fatal so again deficiencies specific to the SOC would not be reported. Sound Localization System The ability to localize sounds in space is accomplished by comparing the signals at the two ears. The comparison can be in the difference in the time of arrival of the signals at the two ears, viz., interaural time differences (ITDs), or in the difference in sound pressure level of the signals at the two ears, viz., interaural level differences (ILDs). The SOC is considered to be the initial site where these binaural comparisons are made. Chapter 14 discusses binaural hearing, and specifically sound localization, in more detail). Figure 7–11 displays these binaural cues measured with miniature microphones placed deep in the rabbit’s ears to a broad band sound from 5 locations along the horizontal plane in an anechoic chamber. The traces in the upper panel for each location display the time waveforms recorded at each ear, whereas the lower panel displays the response in the frequency domain. For any source off the midline, the sound will reach the closer ear first, creating an ITD. Because the head is an obstacle to sound, the sound at the closer ear will also be louder than that to the distal ear, creating an ILD. The degree to which a sound is attenuated by striking an object, like a head, depends upon the wavelength of the sound relative to the size of the object. If the wavelength is long with respect to the size of the head, then there is minimal attenuation and therefore small ILD. If the wavelength is short (i.e., high frequency) relative to head size, then there is large attenuation and large ILD. This dependence of ILD on frequency can be clearly seen in the frequency response traces of Figure 7–11, that show increasing divergence of the left and right ear traces as a function of frequency. It follows that ILDs are an important cue to localize high-frequency sound sources. In contrast, ITDs are an important cue to localize low frequency sound sources because the neural timing information needed to convey ITDs is present in auditory nerve fibers, only for frequencies below ~2 kHz. This dichotomy between the mechanisms for localizing low- and high-frequency signals was formulated long ago (Rayleigh, 1907) and is often referred to as the Duplex theory. Interestingly, the main nuclei of the SOC, the LSO and MSO, can be The Superior Olivary Complex Figure 7–11. Acoustic recordings made in the ear canals of a rabbit to a broad band sound from 5 different spatial locations along the horizontal meridian. Upper panels depict the time waveform from the left (blue) and right (red) ear and corresponding lower panels depict the power spectrum. viewed as the structural basis for the Duplex theory: ITDs are encoded in the MSO whereas ILDs are encoded in the LSO. The frequency dichotomy expressed in the Duplex theory is reflected in the distribution of best frequencies in the MSO and LSO. As can be seen in Figure 7–12, both the LSO and the MNTB have a disproportionate number of neurons tuned to high frequencies in accord with the role of the LSO for encoding ILDs (Guinan et al., 1972). On the other hand, there is the opposite bias in the MSO with a disproportionate representation of low frequencies and neurons sensitive to ITDs. The inputs to the MSO and LSO are illustrated in Figure 7–13. The MSO receives excitatory (glutamatergic) inputs from spherical bushy cells in the VCN of both sides (see Figure 7–13A). In addition it also receives inhibitory (glycinergic) inputs from the ipsilateral LNTB and MNTB that may be the source of ipsilateral- and contralateral-induced inhibition, 171 172 Translational Perspectives in Auditory Neuroscience: Normal Aspects of Hearing dreau & Tsuchitani, 1970). As expected, the receptive fields of LSO cells are such that they respond to stimuli in the ipsilateral sound field and are turned off by sounds in the contralateral sound field. Processing of ITDs Figure 7–12. Tonotopic organization of the LSO, MSO, and MNTB in the cat. Based on Guinan et al. (1972) and Boudreau and Tsuchitani (1970). respectively, since globular bushy cells provide excitatory input to the ipsilateral LNTB and contralateral MNTB (Smith et al., 1991; Cant & Hyson, 1992). The LSO receives excitatory input from spherical bushy cells in the ipsilateral cochlear nucleus (see Figure 7–13B). The input from the contralateral CN originates from globular bushy cells whose axons cross the midline and synapse onto principal cells in the MNTB with one of the most remarkable synapses in the brain: the giant calyces of Held (Tolbert et al., 1982). In turn, the axons of the principal cells in the MNTB make inhibitory glycinergic (Moore & Caspary, 1983) synapses onto LSO neurons of the same side (Spangler et al., 1985). In rat, another source of inhibitory input to the LSO is from the contralateral VNTB (Warr & Beck, 1996). Planar multipolar cells in the DCN may also project to the ipsilateral LSO in the rat (Doucet & Ryugo, 2003). The result of these inputs is that LSO cells are excited by stimulation of the ipsilateral ear and inhibited by stimulation of the contralateral ear, so-called IE cells, thereby making them sensitive to the ILD between the two ears (Bou- In order for a neuron to encode ITDs, the inputs from each ear must reflect the temporal structure of the sound waveforms at each ear. For tonal sounds, this feature is called phase-locking. Phase-locking begins to roll off around 1 kHz in most species. The exception is the barn owl where phase-locking is seen to ~9 kHz. The frequency limits of phase-locking dictates the frequency limit for ITD sensitivity. So, for most mammals with low frequency hearing, the bulk of the neurons prefer ITD at frequencies below ~1.5 kHz, but can extend to 2 to 3 kHz in the cat. The barn owl can show ITD sensitivity to about 10 kHz. In humans, the limit is about 1.1 kHz. The type of ITD sensitivity is dependent on whether the inputs from each ear are excitatory or inhibitory. Figure 7–14 represents the predicted response of a MSO (see Figures 7–15A and 7–15B) or LSO (see Figures 7–14C and 7–14D) neuron to low frequency tonal stimulation that arrive in-phase (Figures 7–14A and 7–14C) or out-of-phase (Figures 7–14B and 7–14D) between the ears. The inputs to these neurons have action potentials that are temporally locked to the tonal waveform and this feature is referred to as phase-locking (Joris et al., 1994). The MSO neuron receives phase-locked excitatory inputs (see Figure 7–14, column 2) from either ear and the LSO neuron (see Figures 7–14C and 7–14D) receives excitatory input from the ipsilateral ear and inhibitory input from the contralateral ear (re: to the side of the LSO cell). Shown for both the MSO and LSO are cases when the ITD is such that the inputs from each ear arrive coincident in time (in-phase, see Figures 7–14A and 7–14C) or when they arrive maximally discordant in time (out-of-phase, see Figures 7–14B and 7–14D). For the model MSO neuron, the phaselocked, action potentials from each ear evoke phaselocked, excitatory postsynaptic potentials (EPSPs, see Figure 7–14, column 3). In contrast, for the LSO neuron, the phase-locked, action potentials from the The Superior Olivary Complex Figure 7–13. Schematic of the medial superior olive (MSO) circuit (A) and the lateral superior olive (LSO) circuit (B). Abbreviations: dorsal (DCN) and ventral (VCN) cochlear nucleus, spinal trigeminal tract (STT), medial (MNTB), ventral (VNTB), and lateral (LNTB) nuclei of the trapezoid body (TB), dorsal lateral (DLPO) and dorsal medial (DMPO) periolivary nuclei, pyramidal tract (PT). contralateral ear evokes phase-locked, inhibitory post synaptic potentials (IPSPs) and those to ipsilateral stimulation evoke phase-locked EPSPs. For the MSO neuron, when the inputs arrive coincident in time (see Figure 7–14A), the EPSPs from each side optimally sum, creating suprathreshold EPSPs (see Figure 7–14A, column 4) and a maximal discharge of action potentials (see Figure 7–14A, column 5). Under the same conditions for the model LSO neuron (see Figure 7–14C), the EPSPs and IPSPs cancel each other and no action potentials are discharged. In the case where the inputs arrive discordant in time, the model MSO neuron is minimally excited (see Figure 7–14B) whereas the model LSO neuron is maximally activated (see Figure 7–14D, column 4 and 5). When the ITD is systematically varied, the ITD functions for the model MSO and LSO show a cyclic function at the period of the stimulating frequency (see Figure 7–14, column 6). At maximum coincidence (0 ITD) the MSO neuron fires maximally 173 174 Translational Perspectives in Auditory Neuroscience: Normal Aspects of Hearing Figure 7–14. A neural schema of ITD processing for model MSO and LSO neurons. The MSO neuron (A and B) receives excitatory (+) inputs from each side, and the LSO neuron (C and D) receives excitatory inputs from the ipsilateral side and inhibitory inputs (-) from the contralateral side. Column 1: 5 cycles of a low frequency tone delivered to the contralateral (blue trace) and ipsilateral (red trace) ear either in-phase (A & C) or out-of-phase (B & D). Column 2. Schematic of action potentials (spikes) phase locked to the stimulating tone that synapse onto a MSO (A & B) or LSO (C & D) neuron. Column 3. Postsynaptic potentials evoked by the contralateral and ipsilateral phase locked spikes. Column 4. Summed postsynaptic responses to binaural stimulation. Threshold for action potentials is indicated by arrows and is lower in the LSO cell (C & D) than for the MSO cell (A & B). Column 5. Schematic of the spike output as a result of the summed postsynaptic potentials exceeding action potential threshold. Column 6. Schematic of the ITD functions for the model MSO and LSO when the ITD is systematically varied. whereas the LSO neuron fires minimally. Note that at maximal activation the MSO neuron exceeds its monaural inputs whereas the maximum response of the LSO neuron does not exceed its ipsilateral input. As the ITD function is cyclic when the ITD of a tone is varied (see Figure 7–14, column 6), it is not possible to determine whether coincidence evokes maximum excitation or suppression using a single tonal stimulus. If the mechanism proposed in Figure 7–14 is operating, then the ITD functions across multiple frequencies should show alignment of the maximum discharge (peak) for MSO neurons and alignment of the minimal discharge (trough) for LSO neurons. This prediction is illustrated in Figure 7–15. For the model MSO neuron (Figure 7–15A ), the ITD functions at different stimulating frequencies (500 to 1500 Hz) show a peak discharge that align at a common ITD, in this case, when the ipsilateral tone is delayed by 150 µsec relative to the contralateral tone. In contrast to the model MSO neuron, the The Superior Olivary Complex Figure 7–15. Schematic of a peak (A–C) and a trough (D–F) type neuron. A and D. ITD functions across frequency for a peak and trough type neuron, respectively. B and E. Composite curve derived from averaging the functions in A and D. C and F. Linear fit of mean interaural phase versus stimulus frequency for a peak and trough type neuron. Characteristic phase (CP) is the phase intercept at 0 Hz and the characteristic delay (CD) is the slope of the linear fit. ITD functions for the model LSO neuron display a minimum (trough) at a common ITD, in this case, when the ipsilateral stimulus is delayed by 150 µsec (Figure 7–15D). The middle panels (Figures 7–15B and 7–15E) show the composite curves derived by averaging the ITD functions in the corresponding panels. The composite curve for the MSO neuron has a peak at 150 µsec whereas that for the LSO neuron has a trough at 150 µsec. The alignment of the peaks or troughs of the ITD functions was first observed in the IC by Rose et al. (1966), and the ITD where this alignment occurred was called the “characteristic delay” (CD). They hypothesized that the CD reflected a difference in the anatomical delays required to activate the binaural cell. By offsetting the difference in anatomical delays with an ITD, the inputs from each ear would arrive simultaneously at the binaural neuron and maximally excite or inhibit it. The quantitative analysis of CDs was developed later by Yin and Kuwada (1983) and is illustrated in the right panels (see Figures 7–15C and 7–15F). The mean interaural phase for maximal discharge for each ITD curve is plotted as a function of stimulating frequency and fitted with a linear regression line. The slope of the regression line represents the CD, and the y-intercept at 0 Hz is the characteristic 175 176 Translational Perspectives in Auditory Neuroscience: Normal Aspects of Hearing phase (CP). For the model MSO neuron, a CP of 0 or equivalently 1 cycle indicates that the CD occurred at maximal discharge (see Figure 7–15C), while for a model LSO neuron a CP of 0.5 cycles indicates that the CD occurred at minimal discharge (see Figure 7–15F). Note that for these idealized neurons, the best delay measured from the composite curves (see Figures 7–15B and 7–15E) matches the CD. The ITD sensitivity of actual MSO and LSO neurons are remarkably similar to the idealized model neurons depicted in Figures 7–14 and 7–15. Figure 7–16 displays the ITD properties of a MSO and LSO neuron recorded in the cat (Tollin & Yin, 2005; Yin & Chan, 1990). Like the model neurons, the peak of the ITD functions across frequency align at the same ITD for the MSO neuron, whereas the trough of the ITD functions across frequency align at the same ITD for the LSO neuron. Also, like the model neurons, the CP for the MSO neuron is near 0 cycles whereas that for the LSO neuron is near 0.5 cycles, and in both cases the CD is similar to the best delay. The representation of ITDs and the neural code for locating a low frequency sound source along the azimuth is a subject of considerable debate (Joris Figure 7–16. Responses of a MSO, peak-type (A–C) and a LSO, trough-type (D–F) neuron. A and D. ITD functions across frequency for the MSO peak and MSO neuron, respectively. B and E. Composite curve derived from averaging the functions in A and D. C and F. Linear fit of mean interaural phase versus stimulus frequency for the MSO and LSO neuron. Characteristic phase (CP) is the phase intercept at 0 Hz and the characteristic delay (CD) is the slope of the linear fit. Panel A adapted from Yin and Chan (1990), with permission of The American Physiological Society. & Yin, 2007). The classic view proposed in 1948 by Lloyd Jeffress (1948) postulated an array of coincidence detectors (e.g., MSO neurons) each with its own set of neural delay lines from each ear that offset the acoustic delays created between the ears from a sound source along the azimuthal plane. In this way an ITD code could be transformed into a place code for sound localization. Many of the anatomic (Beckius et al., 1999; Smith et al., 1993) and physiologic features of the MSO and its inputs have been found to be consistent with the Jeffress model (Batra et al., 1997; Goldberg & Brown, 1969; Spitzer & Semple, 1995; Yin & Chan, 1990; ). However, the finding that the best ITD of a neuron was related to its best frequency and that the peaks of the ITD functions for small-headed animals were often outside of the range that such animals would normally encounter (McAlpine et al., 2001) led to a resurrection of the count comparison model first proposed by von Békésy (1930) and van Bergeijk (1962) that sound localization could be achieved by comparing activity in a structure on one side of the brain with the activity of the equivalent structure on the other side. McAlpine et al.(2001) noted that the medial slope of the ITD functions, independent of the neuron’s best frequency, fell within the physiological range of small-headed animals and changes in ITD would create rapid changes in response rate (also see Skottun et al., 2001). Brand et al. (2002) and Pecka et al. (2008) provided evidence in the MSO of gerbils that inhibitory mechanisms could shift the peaks of the ITD functions outward so that the steep part of this function is always within the physiologic range of the animal. A schema comparing the Jeffress place code model with slope, count comparison model is presented in Figure 7–17. The upper panel depicts an array of ITD-sensitive neurons, each tuned to a particular ITD. Also shown at the top is the range of ITDs encountered by animals with different head sizes. For animals with a small head size (e.g., gerbil, ±125 µsec), the array is limited and only the medial slopes (heavy blue and red lines) fall within the natural range. In this case, the ITD created by a sound source, depending on its location, would create activity on one side of the brain that could be compared with the activity on the opposite side of the brain. In this example, the Jeffress place code The Superior Olivary Complex would be inoperative due to the sparseness of the ITD array. In contrast, for a medium (e.g., cat, ±400 µsec) or large size head (e.g., human, ±825 µsec), the medial slope only constitute a small part of the natural ITD range. So, a Jeffress-type place code would be optimal and ITD created by a sound source would create focused neural activity in the ITD/azimuthal plane. In the middle panel of Figure 7–17, the width of the ITD functions have been broadened. This situation allows the count comparison model to operate for both small and medium head size and a sparse array for animals with a large head size. In the bottom panel, the width of the ITD functions have been broadened even more and here the count comparison model operates over a broad range of head sizes. In summary, when the ITD functions are narrow and dense (see Figure 7–17, upper panel), the count comparison model only operates for small head sizes. As the ITD functions broaden and become sparse, the count comparison model can encompass large and larger head sizes. However, the amount of broadening needed to make the count comparison model work for all head sizes and all frequencies exceeds the physiological evidence (Palmer & Kuwada, 2005). Harper and McAlpine, (2004) concluded that a count comparison mechanism may operate for small-headed animals and a Jeffress place model for large-headed animals. Processing of ILDs While the data presented above argue for a weak role of LSO cells in coding ITDs of complex stimuli, the basic IE response property of LSO cells has traditionally been considered to convey a role in ILD processing (Boudreau & Tsuchitani, 1970). As discussed above, LSO cells receive excitatory inputs from the ipsilateral CN and inhibitory inputs relayed by glycinergic neurons of the MNTB that are in turn excited by the calyces of Held synapses from globular bushy cells of the contralateral CN. The end result is that LSO cells are excited by stimulation of the ipsilateral ear and inhibited by stimulation of the contralateral ear. In this way they are sensitive to the ILD at the two ears. Usually, this has been studied using dichotic stimuli so that the inputs to each ear can be precisely specified. 177 Figure 7–17. Schematic of two models of sound localization. Displayed is an array of ITD-sensitive neurons, each tuned to a particular ITD. The extent of the array depends on the size of the head and in our schematic is shown for ±100 µsec (e.g., gerbil), ±400 µsec (e.g., cat) and ±800 µsec (e.g., humans). The heavy lines centered about an ITD of 0 µsec are the functions used in a slope, count comparison model whereas the entire array are the functions used in a peak-picking or Jeffress model. Top panel: Half-width of ITD functions is 200 µsec; for the middle panel, 800 µsec; and for the bottom panel, 1600 µsec. 178 Figure 7–18 shows responses of an LSO cell illustrating its sensitivity to ILDs. Figures 7–18A through 7–18D show the dot rasters and associated histograms of responses to 300 ms duration best frequency tones (16 kHz) with the ipsilateral excitatory tone held at 30 dB SPL while the contralateral tone is raised from 5 dB SPL (see Figure 7–18A) to 45 dB SPL (see Figure 7–18D). By holding the excitatory ipsilateral stimulus constant, the inhibitory effect of the contralateral input is clearly seen as it is raised in level. The spike count is plotted as a function of ILD (defined as the contralateral level in dB minus the ipsilateral level) in Figure 7–18E. Negative ILDs correspond to higher levels to the ipsilateral ear. ILD sensitivity can be quantified by the half-maximal ILD, which designates the ILD at which the response is half-maximal, and the slope of the function. In Figure 7–18E the half-maximal ILD is about -6 dB. In general, different cells will have different half-maximal ILDs, thereby covering the range of possible ILDs occurring in natural conditions. There are a few reports of systematic topographical representation of half-maximal ILDs across one dimension of a nucleus: cells in the deep and intermediate layers of the superior colliculus (Wise & Irvine, 1985) and in the 60 kHz region of the bat IC (Park & Pollak, 1994). Surprisingly, there are no reports of the receptive field properties of LSO using free-field stimuli. Tollin and Yin ( 2002a) studied the receptive field properties of LSO using virtual space techniques by delivering the stimuli dichotically but filtering the broad band noise by the HRTFs of the cat to simulate sounds at different spatial locations. As expected from the IE binaural property of LSO cells, the spatial receptive fields of LSO neurons had peaks in the ipsilateral sound field where the excitatory ipsilateral input would be dominant and decreased responses in the contralateral field. That the response in the contralateral sound field arose from the inhibition from the contralateral ear was demonstrated by turning off the input to the contralateral ear (Figure 7–19D), a trivial procedure using virtual space stimuli but much more difficult to do in free field. Because ILDs are an inherent component of free-field sound stimuli, vary in a systematic fashion for stimuli in different spatial locations (see Figure 7–11), and strongly modulate the responses of LSO neurons (see Figure 7–18), it is natural to think that The Superior Olivary Complex the shape of the receptive field is determined by the cell’s ILD sensitivity. Taking advantage of the virtual space technique, Tollin and Yin ( 2002b) systematically manipulated the three spatial localization cues of ITDs, ILDs and spectral cues to see which cue was most important in the shape of the receptive field. Figure 7–19 shows an example of the manipulations in one LSO neuron. The idea is to vary only one of the cues while holding the other two cues constant. For example, Figure 7–19A shows results that explore the potency of the ITD cue. The curve labeled “Normal” shows the receptive field of the neuron when all three cues are varied naturally, that is, it shows the receptive field of the cell. The curves labeled Δ-ITD shows responses when the other two cues were held constant at values corresponding to the point straight ahead (ILD = 0 and spectral cues of the straight-ahead position) but ITDs were varied from those values corresponding to -90 deg in the ipsilateral field to +90 deg in the contralateral field. The nearly flat line suggests that ITDs by themselves do not modulate the cell’s response. This is reinforced by the responses in the “0-ITD” condition, where the ITDs were held at 0 and the ILDs and spectral cues varied normally. The close correspondence of the “Normal” and “0-ITD” curves again suggest that ITDs are not important parameters in determining the receptive field response. Figure 7–19B shows analogous manipulations of the spectral cues and the responses are similar to those in Figure 7–19A. These suggest that spectral cues are also not critical in the normal receptive field sensitivity of the cell. Figure 7–19C shows contrasting results when ILDs are studied. In this case the “Normal” and “Δ-ILD” responses are nearly identical, suggesting that ILDs are the key determinant in the normal receptive field response. This is confirmed by the flat response in the “0-ILD” curve which shows that the cell is not modulated by normal variations in ITDs and spectral cues when ILDs are held at 0. While different LSO cells showed different degrees of modulation with the cue manipulation paradigms shown in Figure 7–19, for the most part similar responses were found for all 24 LSO neurons studied. Thus, in accordance with the classical view, ILDs are by far the most important factor in shaping the receptive field profile for most LSO neurons. 179 180 Figure 7–18. Responses of an LSO cell to variations in the ILD of a CF tone. A through D, Dot rasters and PST histograms in response to a 300-msec ipsilateral tone at 30 dB SPL as a function of the level of a tone at the contralateral ear, as shown in the top right of each panel. The inset in A shows the first 40 msec of the response to short tone pips at CF presented monaurally to the ipsilateral ear only, demonstrating the characteristic chopping response exhibited by most of our cells (bin width, 400 μsec and the top tic on the ordinate, 150 spikes). E. Mean discharge rate ±1 SEM versus ILD (in decibels: SPL). (In this and all subsequent figures, where the error bars are not present, the SEM is less than the height of the data point.) The top abscissa indicates the level of the tone at the contralateral ear, and the right ordinate shows the rate normalized to the maximum. The dashed horizontal line shows the spontaneous rate of the unit. Reproduced from Tollin and Yin (2002a) with permission by the Society for Neuroscience via Copyright Clearance Center. The Superior Olivary Complex Figure 7–19. Spatial receptive fields in azimuth for an LSO cell (CF = 7.8 kHz) to cue manipulations of the HRTFs. In all graphs the “Normal” (filled circles) response is that recorded with all localization cues varied naturally. A. ITD manipulations. Responses obtained when the ITD cue was varied normally (∆-ITD) while ILD and spectra were kept constant are shown by filled squares, where as responses when the ITD cue was held constant (0-ITD) are shown by open circles. B. Spectral manipulations. Analogous manipulations as in A except the spectral cue was manipulated. C. ILD manipulations. Same as in A except ILD was manipulated. D. Comparison of the “normal” and ipsilateral stimulus alone responses. Reproduced from Tollin and Yin (2002b) with permission by the Society for Neuroscience via Copyright Clearance Center. As LSO is involved in processing predominantly high-frequency sounds and the human auditory system is chiefly low frequency, a legitimate question is the relative role of the LSO for human hearing. Anatomical, post-mortem studies of the human SOC have generally acknowledged the existence of an LSO though diminished relative to the size of the MSO (Bazwinsky et al., 2003; Moore, 1987; Strominger, 1978). On the other hand, the existence of the MNTB has been controversial (Bazwinsky et al., 2003; Moore, 2000; Richter et al., 1983), which casts doubt on the importance of the ILD circuit in the human system (Schwartz, 1992). Question 2 Is it known how the SOC encodes sound when a patient wears a cochlear implant or brainstem implant? 181 182 Translational Perspectives in Auditory Neuroscience: Normal Aspects of Hearing Answer 2 There are no studies examining the response of SOC neurons to cochlear implant stimulation. However, there are numerous studies that have recorded from the auditory nerve, cochlear nucleus, and inferior colliculus to cochlear implant stimulation. One reason for the lack of studies in the SOC is that, in general, it is a very difficult site to make singleunit recordings. On a different note, there is growing literature in which patients who receive bilateral cochlear implants are tested with one vs. two devices, and it looks like most patients perform significantly better with two implants than with one. As the SOC is the first site where the inputs from each ear converge, it is likely that this effect is mediated through the SOC. Summary We have provided a brief summary of the anatomy and physiology of the cell groups in the SOC. While most previous studies of the SOC have concentrated on the binaural processing which is thought to involve sound localization, the SOC also provides important feedback pathways to the cochlea by the olivocochlear systems as well as intrinsic inhibitory processing networks in the periolivary nuclei. Further Readings Irvine, D. R. F. (1986). The auditory brainstem. In D. Ottoson (Ed.), Progress in sensory physiology (Vol. 7). Berlin, Germany: Springer-Verlag. Yin, T. C. T. (2002). Neural mechanisms of encoding binaural localization cues in the auditory brainstem. In D. Oertel, A. N. Popper, & Fay R. R. (Eds.), Integrative functions in the mammalian auditory pathway (pp. 99–159). New York. NY: Springer-Verlag. References Abou-Madi, L., Pontarotti, P., Tramu, G., Cupo, A., & Eybalin, M. (1987). Coexistence of putative neuroactive substances in lateral olivocochlear neurons of rat and guinea pig. Hearing Research, 30, 135–146. Altschuler, R. A., Fex, J., Parakkal, M. H., & Eckenstein, F. (1984). Colocalization of enkephalin-like and choline acetyltransferase-like immunoreactivities in olivocochlear neurons of the guinea pig. Journal of Histochemistry Cytochemistry, 32, 839–843. Batra, R., Kuwada, S., & Fitzpatrick, D. C. (1997). Sensitivity to interaural temporal disparities of low- and high-frequency neurons in the superior olivary complex. II. 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