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Development of Sound Localization Mechanisms

Abstract and Keywords

Decades of research has demonstrated anatomical, physiological, and behavioral consequences of manipulations of the acoustic sensory environment early in life. These manipulations, either naturally occurring in humans or experimentally induced in laboratory animals, deprive sounds to one or both ears. In this chapter, experience-dependent plasticity in the development of the auditory system is examined with an emphasis on the pathways that subserve binaural and spatial hearing—the coordinated use of information from the two ears for auditory perceptions such as sound location. A balance of inputs from the two ears is necessary for normal development of the central auditory system, and disruption of this balance early in life results in anatomical and physiological reorganization of the binaural auditory pathways and corresponding behavioral deficits.

Keywords: acoustic sensory environment, experience-dependent plasticity, auditory system, binaural hearing, spatial hearing, sound location

Introduction

Auditory-guided behavior depends on the ability of the nervous system to construct an accurate representation of the sounds in the environment. To this end, the auditory system must determine both “what” it was in the environment that produced a sound and “where” in space the sound occurred. Knowledge of both the position of a sound’s source and what produced it facilitates the initiation of an appropriate behavioral response. For example, a predator like a cat might move toward the sound produced by a mouse rustling in the leaves while the mouse might freeze or move away from the sounds of the approaching cat.

Binaural hearing refers to the coordinated use of information from the two ears for auditory perceptions such as sound location. For humans, binaural hearing confers additional important perceptual benefits due to the ability to spatially separate and selectively attend to a particular sound source, such as speech, in the presence of other competing sounds. A typical auditory environment, like an auditorium or classroom, involves multiple and concurrent sound sources. Often referred to as the “cocktail party” phenomenon, our spatial hearing ability substantially increases the comprehension of speech in such noisy and reverberant environments (Yost, 1997). When our binaural and spatial hearing mechanisms are disrupted or do not develop properly, auditory perception in such environments becomes impaired.

The ability to locate sensory stimuli is not unique to the auditory system as it is also shared by the visual and somatosensory systems. The locations of visual and tactile objects are encoded directly in these systems due to the topographic, spatial organization of the receptors, the rods and cones of the retina, and the mechanoreceptors of the skin. (p. 263) In contrast, in the auditory system, the hair cells of the cochlea are designed to encode sound frequency and intensity and have no mechanisms to sense sound location directly (Yin, 2002). Therefore, sound location must be computed centrally in the auditory system based on the neural representations of the spectral and temporal characteristics of the acoustic stimuli arriving at the two ears. Yet the magnitudes of these acoustical cues to sound location and the manner in which they change with sound location are solely dependent on the physical size of the head and external ears. This creates a challenge during development where the growing size of the head and ears increase dramatically, thus also changing substantially the relationship between the acoustical cues and a particular sound location. The final mature size of the head and ears, and thus the final set of acoustical cues for sound location likely cannot be predicted. Therefore, the precise neural circuits mediating localization probably are also not likely to be genetically encoded. An attractive hypothesis, therefore, is that auditory experience early in life calibrates the neural circuits that process sound source location to the exact acoustical properties of the head and ears of each individual.

The terms “critical period” and “sensitive period” are often used to describe the influence of experience on the normal development of a sensory system, although sensitive period is the term most often used. As distinguished by Knudsen (2004), sensitive periods apply when there is an unusually strong influence of experience on brain development during a limited period of time, times during which important behavioral capabilities are easily shaped or altered by environmental influences. In general, the undesirable effects of abnormal experience during a sensitive period cannot be easily remediated by restoring typical experience later in life. But restoration of normal sensory input for brain functions subject to sensitive periods can potentially lead to a remediation of the problem. Naturally, it is of extreme interest to identify what developmental processes are subject to sensitive periods, and what the durations of those periods are so that appropriate clinical diagnoses and interventions can take place.

It has long been known that environmental sensory experience early in life can have profound and long-lasting impacts on behavior later in life. In this chapter, our understanding of experience-dependent plasticity in the developing mammalian auditory system is reviewed with a focus on the neural pathways and mechanisms that subserve binaural and spatial hearing, including sound localization. Experience-dependent refers to plasticity that is dependent upon the acoustical information available only from the interaction of the organism in its present environment. The chapter begins with a description of the basic mechanisms underlying sound localization including a discussion of the acousticalcues to location. The anatomical, physiological, and behavioral consequences of manipulations of the acoustic sensory environment in experimental animals that have been used to induce modifications in the developing auditory system are then examined. These manipulations include limiting or depriving acoustic input to one ear or to both ears. The results of these studies are beginning to paint a picture of a competitive interaction between the developing inputs from both ears. A balance of inputs from the left and right ears appears to be necessary for normal development of the central auditory system, and anything that disrupts this balance early in development results in substantial reorganization of the binaural auditory pathway, both the anatomy and physiology, synaptic structure, and ultimately behavior. Finally, some of the naturally occurring manipulations of the auditory systems in clinical populations are described that have indicated that there is indeed some form of experience-dependent plasticity in the human binaural auditory system.

Development of Sound Localization–A Model System for Experience-dependent Plasticity

Since the classic studies of the development of the binocular visual system by Hubel and Wiesel, it is now a firmly established tenet of developmental neuroscience that the relative sensitivity, or plasticity, of the nervous system to sensory inputs can be altered by manipulations of the sensory environment within some limited time period of early development (Wiesel, 1982). As the organism matures, the degree of plasticity generally diminishes. The results of these and many subsequent studies have shown that abnormal sensory input for a limited period of time early in life, often called the sensitive period (Wiesel & Hubel, 1965), can alter and modify the structure-function relationship of neural circuits, and can therefore have profound effects on perception and behavior and the capacity for such later in life. These findings likely apply to thedevelopment of the auditory system as well, although much less is known. This is ironic (p. 264) because one of the very first conclusive demonstrations of experience-dependent plasticity was in the auditory system, in which Levi-Montalcini (1949) found that depriving neonatal chickens of normal acoustic input resulted in substantial shrinkage, atrophy, and general reorganization in the central auditory pathways. Thus, auditory development is not driven exclusively by genetic factors. One of the goals of basic research in the neurosciences is to determine the relative importance of genetic and molecular mechanisms and experience-dependent influences on the development of neural function so that these findings can be translated into effective clinical interventions. The studies of the development of binaural auditory system focus on these areas of research.

Much in the same way that the binocular visual system provided a good model system for the experience-dependent developmental studies of Hubel and Weisel due to the ability to manipulate the sensory environment of each eye independently, the binaural auditory system also relies on interactions between sensory inputs from two spatially opposed sensory structures, the two ears. The ability to localize sounds results from computations in the central auditory system because the peripheral receptors in the cochlea of each ear have no mechanisms themselves to encode spatial location. In terms of the development of the auditory system, it is known that the structural and functional susceptibility to manipulations of the ear and to environmental influences is by measures of degeneration in at least some auditory nuclei, lost at a very early stage of development, well before the onset of hearing in many experimental animals (Moore & King, 2004). Yet for other auditory system pathways, particularly those subserving binaural interaction, there seems to be a much longer lasting susceptibility to manipulations of the ear and the acoustic environment. This may allow experience-dependent influences to sculpt the final disposition and information processing capabilities of these neural circuits for sound localization.

Sound Localization: The Acoustical Cues and Their Encoding

Acoustical Cues to Sound Source Location

Since the focus of this chapter is on the development and plasticity of the binaural auditory system, it is useful to review the acoustical cues to sound source location and the basic neural mechanisms by which the cues are encoded. There are three primary acoustical characteristics of sounds, or cues, to the spatial position of a sound source (Figure 13.1) (Tollin & Koka, 2009): the interaural time differences (ITDs), interaural level differences (ILDs), and monaural spectral shape cues. The cues are created by three different ways by which the propagating sound waves from a source physically interact with and are modified by the head and external ear before entering the ear canal. The ITD cues result because the two ears are physically separated in space by the head. The direction-dependent differences in path lengths that sound must travel to reach each ear from the source will generate different times of arrival of the sound at the two ears, or ITDs (Figure 13.1B,E). The ILDs result from the fact that the two ears are separated by an obstacle, the head. For sounds of high frequency (or wavelengths shorter than the diameter of the head), the head casts an acoustic shadow. Consequently, the resulting sound arriving at the ear farthest from the source is attenuated (Figure 13.1B), thereby creating direction- and frequency-dependent differences in the amplitudes, or levels, of the sounds that reach the two ears (Figure 13.1C,D). The ITD and ILD cues are used primarily for localizing sounds varying in azimuth, but are not useful for localization in elevation because their values change little with variations in source elevation. The so-called monaural spectral shape cues, however, do change systematically with source elevation. Spectral shape cues arise from direction- and frequency-dependent reflection and diffraction of the pressure waveforms of sounds by the head, torso, and pinnae that result in broadband spectral patterns, or shapes, that change with location (e.g., the deep “notches” that occur at some locations, like 5.5 and 9.5 kHz for the left and right ear, respectively, in Figure 13.1C).

Neural Encoding of the Acoustical Cues to Sound Location

Development of Sound Localization Mechanisms

Figure 13.1 The acoustical cues to sound location. In the example, the cues are shown for the cat, but the same three cues are available in all species, although the magnitude of the cues will be different. (A) A broadband transient sound is presented from a loudspeaker at (-40°,0°). (B) The resulting acoustical responses to the transient near the eardrums in the left (red) and right (blue) ears. The difference in the onset times of the sounds at each ear yields the interaural time difference (ITD) cue and difference in amplitudes reflect the interaural level difference (ILD) cue. (C) The frequency spectrum of the acoustical responses in B. The spectral shape cues are captured by the changes in the patterns of the sound spectra as a function of source location. The ILD cue is the difference in sound level computed at each frequency. (D) The joint spatial and frequency dependence of ILDs for sources varying along the horizontal plane. ILDs are a complicated function of azimuth and frequency for high-stimulus frequencies. (E) The ITD plotted as a function of sound source azimuth. ITDs are minimal near the midline and maximal for sources to either side. For illustrative purposes, sources were restricted to the horizontal plane for frequencies between 1 and 25 kHz. (Data computed from Tollin & Koka, 2009.)

The three localization cues are initially extracted and encoded at a very early stage in the ascending auditory system. There are three parallel pathways through the brain stem that encode separately the ITD, ILD, and spectral cues. Figure 13.2 shows the pathways that are involved in the central processing of sound location from the cochlea through the auditory brain stem, midbrain, and finally to the primary auditory cortex; note that only one “half” of the ascending auditory pathway is represented in Figure 13.2. Sound entering the external ears ultimately stimulates the peripheral auditory receptors, (p. 265) the hair cells, initiating the transduction of airborne sound into spatiotemporal patterns of neural activity in the array of auditory nerve fibers (ANFs; see Ruggero, 1992). As a result of the mechanical frequency analysis of sound by the cochlea, the ascending system is organized according to sound frequency. That is, there is tonotopic organization, which refers to the fact that the neurons within the nuclei depicted in Figure 13.2 are arranged according to their frequency selectivity.

Development of Sound Localization Mechanisms

Figure 13.2 Illustration of a frontal section through the mammalian brain stem showing the ascending pathways from the cochlea through the primary auditory cortex (A1). (A) The pathways through the main binaural auditory nuclei when stimulated with a sound source on the right side are highlighted in this figure. The lateral superior olive (LSO), which is believed to be responsible for encoding interaural level differences (ILDs), receives bilateral inputs from both ears. The inputs from the ipsilateral ear (right) via the neurons of the anteroventral cochlear nucleus (AVCN, or just CN) are excitatory (open symbols) but the inputs from the contra-lateral ear (left) are inhibitory (filled symbols) due to the additional synapse in the ipsilateral medial nucleus of the trapezoid body (MNTB). AVCN neurons receive inputs from the auditory nerve fibers (ANFs) via the hair cells of the cochlea. The ipsilateral excitation and contralateral inhibition allows LSO neurons to encode ILDs (panel C). LSO neurons send excitatory projections to the contralateral inferior colliculus (IC) and dorsal nucleus of the lateral lemniscus (DNLL, not shown) and inhibitory projections to the ipsilateral IC and DNLL. Neurons of the medial superior olive (MSO) receive bilateral excitatory inputs from both ears via AVCN. MSO neurons encode the interaural time difference (ITD) cue (panel B). MSO neurons send an excitatory projection to the ipsilateral inferior colliculus (IC) and DNLL (not shown). Finally, neurons in the AVCN send excitatory projections primarily to the contralateral IC, but there is also a small projection to the ipsilateral IC (not shown). The auditory thalamus, the medial geniculate body (MGB), receives input primarily from the ipsilateral IC and sends projections to the ipsilateral A1. The color bar and shading indicates the tonotopic organization of these nuclei for the cat.

Specific details of how each of these cues are encoded by these neural circuits are reviewed in great detail elsewhere (ITD: Yin, 2002; spectral cues: Young & Davis, 2002; ILD: Tollin, 2003; Tollin, 2008). In short, spectral cues are thought to be encoded in the dorsal cochlear nucleus (DCN), which will not be discussed here. The ITD and ILD cues are encoded in two parallel circuits in the superior olivary complex (SOC). The SOC contains two nuclei, the lateral (LSO) and medial superior olive (MSO), which are the first major sites in the ascending auditory pathway to receive inputs from both ears. The SOC is essential for sound localization; cutting the afferents to the SOC (Masterton, Jane, & Diamond, 1967; Moore, Casseday, & Neff, 1974) or lesioning the cell bodies of the SOC itself (Kavanagh & Kelly, 1992) dramatically disrupts behavioral localization (p. 266) ability. The LSO and MSO separately extract the ILD and ITD cues, respectively. LSO and MSO neurons project to the inferior colliculus (IC), an obligatory relay site in the midbrain where virtually all the auditory circuits that have diverged into multiple streams in the brain stem by and large reconverge (Winer & Schreiner, 2005). In terms of sound localization, most IC neurons are sensitive to sound sources in the contralateral hemifield.

Reflecting the importance of the IC for localization, lesions of its output pathways or the IC itself results in severe deficits in localization performance in animals (Jenkins & Masterton, 1982; Kelly & Kavanagh, 1994) and humans (Litovsky, Fligor, & Tramo, 2002), particularly for sources in the hemisphere contralateral to the lesion.

Sensitivity to ILD cues in LSO neurons results because they are inhibited by sounds to the (p. 267) contralateral ear and excited by sounds to the ipsilateral ear (Figure 13.2A). The input from the ipsilateral ear (right ear in Figure 13.2) is conveyed via ANF projections to the cochlear nucleus (CN), which then sends an excitatory projection to the ipsilateral LSO. The afferent input from the contralateral ear (left ear in Figure 13.2) also comes from the CN, but in this case, the axons project across the midline to the medial nucleus of the trapezoid body (MNTB). MNTB neurons are glycinergic, so their projection to the LSO has an inhibitory effect. Because of the interplay of the ipsilateral excitation from the CN and contralateral inhibition from the MNTB, LSO neurons essentially compute the difference between the neural representations of the sound levels present at the two ears. Hence, LSO neurons encode ILDs. LSO neurons respond best to ipsilateral sound sources that produce ILDs favoring the excitatory ear (Figure 13.2C; Tollin & Yin, 2002; Tollin, Koka, & Tsai, 2008). LSO neurons project bilaterally to the IC. In order to achieve the contralateral representation of space that is a basic feature of higher sensory and motor areas of the brain, LSO neurons send excitatory projections to the contralateral IC and predominantly inhibitory projections to the ipsilateral IC. As a result, most neurons in the IC respond best to contralateral sound sources (e.g., sounds at the right ear in Figure 13.2A) as depicted in Figure 13.2C.

The MSO neurons receive excitatory inputs from the CN on both sides. Via a process called phase locking, the afferents to MSO from the CN on both sides encode the relative time differences (i.e., ITDs) in terms of the precise encoding of the ongoing sound waveform via the trains of action potentials. MSO neurons act as coincidence detectors, increasing their responses when action potentials arrive nearly simultaneously from the left and right ear afferents but decreasing their responses when they do not arrive simultaneously (Figure 13.2B). Although beyond the scope of this chapter (see Yin, 2002), as shown in the figure, the MSO encodes ITDs for sounds located primarily in the contralateral field (i.e., contralateral to the MSO). Unlike the LSO, the excitatory outputs from the MSO innervate only the ipsilateral IC. Consequently, IC neurons that are sensitive to ITDs encode sounds in the contralateral field (Figure 13.2B; Palmer & Kuwada, 2005).

Finally, the CN, including the DCN, which encodes the spectral shape cues to sound elevation, also projects to the IC, but the projection is highly asymmetric, with the IC receiving excitatory input predominantly from the contralateral CN and very little input from the ipsilateral CN (Figure 13.2; Winer & Schriner, 2005). Because of the large- scale convergence of these ascending inputs from the MSO, LSO, CN, and other brain stem nuclei to the IC, it is thought that the IC may represent a site in the auditory pathway that is particularly amenable to developmental and experience-dependent plasticity (Yu, Sanes, Aristizabal, Wadghiri, & Turnbull, 2007).

Why Should the Localization System Be Plastic? Developmental Challenges Faced by the Binaural Auditory System

Why should the neural circuits mediating sound localization and binaural hearing be plastic early in development? And why should auditory system pathways specifically subserving binaural interaction exhibit a longer lasting susceptibility to manipulations of the ear and the acoustic environment (Moore & King, 2004)? Some newborn mammals, including human infants (Muir & Field, 1979; Wertheimer, 1961), have some capability to make orienting movements to the location of sounds immediately at or shortly after birth. For example, kittens, a common animal model for the development of the auditory system, can reliably approach sounds by 24 days of age (~2 weeks after hearing onset), although with considerably less accuracy and precision than adult cats (Clements & Kelly, 1978).

The ability of humans, kittens, and other infant animals to make overt orienting responses to sounds suggests that the basic organization of the binaural system may be established early in development. But physiological and simple reflexive behavioral responses to sounds in general are typically seen much earlier, around the time of birth for cats and in utero for humans (Rubsamen & Lippe, 1998). Moreover, sound localization acuity in humans does not mature until 5 years of age or older (Litovsky & Ashmead, 1994). The apparent delay in directional responding and the long period until sound localization acuity is mature might be related to a slower rate of development of the binaural hearing mechanism, the specific cues for location, or simply motor control. Whatever the reason, a behavioral directional response to sound likely requires at least some development of the central auditory system beyond that needed to respond simply to general acoustic information. This is because accurate localization requires that the specialized binaural mechanisms discussed above (Figure 13.2) (p. 268) be in place to process the cues involved in sound localization (Figure 13.1) and ultimately make the correct association of these cues with the appropriate spatial locations.

Evidence from animal models confirms that the rough circuitry of the binaural auditory system appears to be in place and largely functional even while the peripheral auditory system is still developing. For example, neurons in the LSO (Sanes & Rubel, 1988) and IC (Blatchley & Brugge, 1990; Clopton & Silverman, 1977) are crudely sensitive to the ILD cue to sound localization (Figure 13.1) shortly after the onset of hearing. Developmental studies of ILD sensitivity of neurons in the IC, which receives input from the LSO (Figure 13.2), show some adult-like ILD sensitivity at the onset of hearing in the cat (Blatchley & Brugge 1990), but other studies do not report adult-like sensitivity until 31–40 days postnatal (Moore & Irvine, 1981). By adult-like, it is meant that individual neurons respond over a range of acoustic ILD cues (dynamic range) similar to that found in adult animals. Neurons in the IC of infant cats are also sensitive to ITDs (Blatchley & Brugge, 1990), with some neurons appearing adult-like in their ability to process ITD. Yet other important aspects of the responses are not even close to adult-like, such as the maximum discharge rate, the slopes of the functions relating the response of the neuron to the sound localization cues, and the neural response variance (Sanes & Rubel, 1988; Seidl & Grothe, 2005). These results indicate that while the subcortical neural circuits mediating sensitivity to ITD and ILD are in place and largely capable of some rudimentary function at a very early age, there are still considerable changes that take place during development. The early establishment of the binaural anatomy may allow auditory experience to exert its effects on the binaural system through experience-dependent plasticity. In precocial mammals, such as humans and chinchillas, some of this development likely takes place in utero through the sounds experienced there. However, since much of this early patterning of the auditory system occurs prior to the emergence of electrical activity in auditory neurons, the establishment of these circuits is likely guided by activity-independent factors (see Friauf, 2004). But the experience-dependent sculpting of these circuits later in development ultimately allows for the subtle variations in processing that are necessary to accommodate the organism in its current environment.

One of the purposes of a sensitive period in the development of binaural and spatial hearing might be to accommodate the large changes in the acoustical cues to location that are experienced during development due to growth of the head and ears. Plasticity during development would allow a precise calibration of the neural circuits for spatial hearing to the actual values of the cues associated with the individual. During development, the diameter of the human head nearly doubles (Clifton, Gwiazda, Bauer, Clarkson, & Held, 1988); the same is true for the cat (Tollin & Koka, 2009). That is, the two ears of an adult are not only twice as far apart but are also separated by a much larger obstacle than in an infant. Therefore, the values of ITD at any horizontal location will be roughly twice as large. The ILD values will not only be considerably larger at any one sound frequency due to the larger effect of the head shadow, but also be generated for lower frequencies. There seems to be little effect on behavior of the changing cues due to development since infant and juvenile animals and humans have at least some capacity to localize/orient to sound sources with a decent degree of accuracy (Clements & Kelly, 1978). This would not be possible if the animals were simply interpreting their immature acoustical cues in terms of a genetically predisposed adult mapping of cue values to location. Thus, sound localization behavior appears to be adapting as the cues themselves change.

Experience-dependent Development of the Binaural Auditory System

There are both activity-independent and activity-dependent processes in the development of the auditory system (Rubel, Parks, & Zirpel, 2004). For example, the development of the crude tonotopic organization of the auditory system (the topographic organization based on sound frequency) and the rough anatomical connections between appropriate nuclei and between the two ears is most likely determined via molecular markers that are controlled largely via activity-independent mechanisms (Rubel et al., 2004). Activity-dependent processes on the other hand are thought to exert their affects later in development to control cell growth and death, axonal and dendritic pruning and growth, synaptic strength, and thus the fine-tuning of the circuits. Because many neurons in the normal auditory system are spontaneously active in the absence of auditory input, activity-dependent processes are not necessarily the same as experience-dependent processes. In fact, (p. 269) there are spontaneous responses in the peripheral auditory system prior to hearing onset (Lippe, 1994). As discussed below, the competitive interactions necessary for the development of the binaural auditory system require at least some balanced activity from the two sides (left and right ears), be it due to evoked responses from normal acoustical input or from the spontaneous activity of afferent fibers. Development of sound localization capability, then, seems to be a joint product of genetics and experience-dependent plasticity.

In order to study the experience-dependent role of acoustic stimulation on development, experimental manipulations of the peripheral parts of the ear have been employed to deprive the system of acoustic inputs. Using acoustic sensory deprivation gives the experimenter some control over the acoustic environment that an animal is reared in. Studies in such animals have revealed a variety of changes in central auditory neurons following experimentally induced or naturally occurring deafness. Depriving experimental animals (or humans) of normal auditory input during restricted periods of early development alters the normal formation of neural circuits for sound localization in an often irreversible fashion. Based on such experiments, it has been hypothesized that in the development of binaural and spatial hearing, a competition between the two ears takes place for synaptic space on binaurally innervated neurons in the auditory brain stem (Moore, Hutchings, King, & Kowalchuk,1989). This hypothesis is examined in the following section.

Acoustic Deprivation–Control of Sensory Experience

There are several different methods that have been used to modify the acoustic experience in experimental animals to study the experience-dependent aspects of auditory system development. Two techniques have been most commonly used: (1) conductive hearing losses that interfere mechanically with the normal acoustic input pathways to the inner ear and (2) sensorineural hearing losses that directly interfere with the neural transduction mechanisms, either by removing or damaging the cochlea, hair cells, and/or ANF array. The former modifies the acoustic input, which simply reduces, but does not eliminate, the overall level of sound-evoked activity in the peripheral auditory system. While conductive losses have no effect on spontaneous activity levels, sensorineural manipulation reduces or, in many cases, even abolishes both sound-evoked and spontaneous activity (Tucci, Born, & Rubel, 1987). It has to be kept in mind that studies that have used these techniques to examine the sensitive period in the development of the auditory system have been complicated by the fact that most procedures used to deprive the experimental animals of normal auditory experience have been either irreversible (cochlear ablation, hair cell destruction, etc.), or if they were reversible (ear plugs, ear canal atresia, etc.), they do not provide sufficient deprivation of sound to eliminate all neural activity. Moreover, even with the latter, less invasive type of deprivation, it has typically not been demonstrated by the experimenter that some form of sensorineural hearing loss did not develop as an unintended consequence of the manipulation.

There are many good experimental and logical reasons for using both kinds of deprivation techniques. Conductive hearing losses are of interest because they are potentially reversible (e.g., ear plugs) and do not typically result in any peripheral neuron death (discussed below). Moreover, the spontaneous activity of peripheral neurons is preserved. With this technique, the auditory system can be tested for functionality at some time after the deprivation. For example, behavioral and/or neural responses to sounds of interest presented to the manipulated ear could be examined. Complete, but reversible auditory deprivation is difficult to achieve in experimental animals because simply occluding an ear to airborne sound does not preclude bone-conducted sound. The final advantage is that conductive hearing losses simulate known human hearing disorders. The sensorineural method induces complete irreversible damage of the inner ear (via ototoxic drug exposure, noise exposure, or ablation of the cochlea). This method has the advantage that it typically results in complete removal of not only sound-evoked but also spontaneous neural activity. Clearly the limitation of this technique is that it does not allow for the testing of the physiological or behavioral consequences of the manipulated ear at some later age because there is typically substantial peripheral neuron death (although such systems can be stimulated electrically). Moreover, sensorineural manipulations do not really simulate any common human hearing disorders (Moore & King, 2004). Therefore, the clinical value of such experiments may not be informative for human auditory pathology.

In the following discussion of the anatomical, physiological, and behavioral consequences of (p. 270) unilateral (one ear) and bilateral (both ears) sound deprivation, reference will not be made to what kind of experimental manipulation (conductive or sensorineural) was employed, unless it is critical for the interpretation of the data. However, there are two critically important differences in the outcomes of experiments using the two different techniques that should be kept in mind. These differences depend on the age of the animal. First, in altricial animals (which are born deaf), peripheral neurons (ANF, CN, etc.) are lost (neuron death) in massive numbers when cochlear ablation is induced before the onset of hearing function (Hashisaki & Rubel, 1989; Tierney, Russell, & Moore, 1997). This seems to be the result of abolishing the intrinsic spontaneous activity that is present in peripheral auditory neurons even before hearing onset (Lippe, 1994). It is known that destroying the cochlea (Koerber, Pfeiffer, Warr, & Kiang, 1966) or chemically silencing the electrical activity of hair cells (Pasic, Moore, & Rubel, 1994) abolishes spontaneous activity in central auditory neurons. Thus, there appears to be a correlation between hearing onset and neuron loss in response to a peripheral sensorineural hearing loss. If cochlear ablation or hair cell activity silencing occurs prior to hearing onset, there is neuron loss on a massive scale; if the cochlear ablation or hair cell activity silencing is near hearing onset or after, there is no neuron loss, only soma shrinkage and a reduction in the volume of auditory nuclei (CN, LSO, etc., Figure 13.2) that receive excitatory input from the manipulated ear as well as other synaptic changes that will be discussed below. Conductive hearing losses induced at any point during development do not result in neuron death, but can result in substantial reduction in neuron size and nucleus volume and can lead to large-scale synaptic modifications. Finally, as stated earlier, experiments employing sensorineural hearing losses do not allow for functional assessment of the system, behaviorally or neurally, at a later time period.

Monaural Sound Deprivation–A Case of “Use It or Lose It?”

Development of Sound Localization Mechanisms

Figure 13.3 Illustration of the normal auditory pathways through the inferior colliculus (IC). See Figure 13.2 for details. (A) The inputs to the ICs of both sides are balanced in the normal auditory system. (B) After unilateral deprivation of the right ear, there are large-scale changes in the balance of the ascending pathways to the ICs. The auditory nerve (not shown), cochlear nucleus (CN), medial nucleus of the trapezoid body (MNTB, not shown), lateral superior olive (LSO), and IC all exhibit volume reductions, neuron shrinkage and/ or death, and morphological and synaptic changes, as indicated by the smaller size of the nucleus in the figure. Moreover, the patterns and strengths of projections to the IC from the brain stem nuclei are altered, as indicated by increases or reductions in the widths of the projections relative to normal (panel A). After bilateral deprivation (not shown), the circuit resembles the normal-hearing circuit in A.

The studies reviewed here on the development of the auditory system suggest that early deprivation of auditory experience can produce structural and organizational changes in the auditory pathway. Here the anatomical, physiological, and then behavioral consequences of monaural sound deprivation are discussed, with an emphasis on how this manipulation affects binaural and spatial hearing. Figure 13.3A shows a simplified schematic of the (p. 271) anatomical pathways from the CN through to the IC (see Figure 13.2 for details). The relative size of the arrows roughly indicates the number and strength of the neural projections between nuclei. The shading indicates excitatory (open) or inhibitory (shaded) connections. In the normally developed auditory system, the inputs from the two sides of the brain stem to the ICs on both sides are balanced. In the following, the changes that occur to this circuit due to altered auditory experience are examined.

Anatomical Changes

Neonatal animals raised with a unilateral hearing loss (right ear, Figure 13.2B) of either type, conductive or sensorineural, show profound changes in the anatomy of the ascending auditory system. The auditory nerve shrinks or dies (not shown in Figure 13.2B; Hardie & Shepherd, 1999; Moore et al., 1989; Moore & Kowalchuk, 1988; Webster, 1983a, 1983b) and there is a large decrease in the size and density of neurons in the ipsilateral CN on the affected side, particularly in the ventral regions of the CN, whose neurons send projections to the MSO and LSO for sound localization (Figure 13.2B; Blatchley, Williams, & Coleman, 1983; Coleman, Blatchley, & Williams, 1982; Coleman & O’Connor, 1979; Hardie & Shepherd, 1999; Moore et al., 1989; Moore & Kowalchuk, 1988; Nordeen, Killackey, & Kitzes, 1983; Tierney et al., 1997; Trune, 1982a, 1982b; Webster, 1983a, 1983b, 1988; Webster & Webster, 1977, 1979). The crosssectional area of the dendritic fields of CN neurons ipsilateral to the affected ear are reduced by half (Trune, 1982b). The auditory nerve and CN on the side of the unaffected ear are largely normal. These observed effects are illustrated in Figure 13.2B by the reduction in size of the CN on the side of the manipulated ear (right ear).

The effects of monaural deprivation on the morphology of these peripheral neurons tended to depend upon the age at which the deprivation occurred. In rats, Blatchley et al. (1983) found that neurons in the ventral cochlear nucleus (VCN) were most affected when the deprivation was initiated between 10 and 16 days after birth. As the deprivation was initiated later, the effects on the VCN were reduced. Webster (1983b) found a similar trend in mice were a unilateral conductive loss had the most effect on VCN cell size and volume if the loss spanned a restricted period from 12 to 24 days after birth. Deprivation ending before 12 days or initiated after 24 days resulted in little change in the VCN. Other studies have shown little effect of conductive hearing losses on VCN neuron size or volume (Moore et al., 1989). The reasons for these discrepancies are not known.

The binaural nuclei are also affected by unilateral manipulations of the ear. Removing or reducing sound-evoked (and spontaneous) activity from one side clearly disrupts the balance of neural inputs to the MSO and LSO. The normal balance of inputs to these nuclei (Figure 13.3A) is reduced (conductive loss) or eliminated (sensorineural loss), and as such, the ability of MSO and LSO neurons to process the binaural cues to sound location, ITD and ILDs, respectively, will also be disrupted. Anatomically, unilateral cochlear ablation in adult cats produced shrinkage of neurons in ipsilateral LSO (right side, Figure 13.3B) and contralateral MNTB (not shown), but no loss of neurons (Powell & Erulkar, 1962). Conductive losses also produce substantial neuron shrinkage in contralateral MNTB (Moore, 1992; Webster, 1983a, 1983b). Pasic et al. (1994) reported substantial neuron shrinkage, but no loss of contralateral MNTB in response to chemical blockade of electrical activity in the cochleas of juvenile, but not infant, gerbils. Neurons in the LSO ipsilateral to the manipulated ear (Figure 13.3B) also exhibit profound shrinkage (conductive loss: Webster, 1983a, 1983b) and loss (sensorineural loss: Moore, 1992). There are also substantial morphological changes in the dendritic arbors of LSO neurons (Sanes, Markowitz, Bernstein, & Wardlow, 1992). Interestingly, LSO neurons contralateral to the manipulated ear (left side, Figure 13.3B) do not show shrinkage or loss. Recall that LSO receives inputs from both ears (Figure 13.2), that is, excitation from the ipsilateral and inhibition from the contralateral ear. The fact that LSO neurons ipsilateral but not contralateral to the manipulated ear show shrinkage and loss suggests that the contralateral inhibitory input to the LSO ipsilateral to the manipulation is not sufficient to maintain the LSO (Moore, 1992). Excitatory synapses appear to be required to strengthen and maintain synaptic connections, neuron size, and nucleus volume.

In support of this hypothesis, unilateral manipulations do not lead to neuron shrinkage or loss in the MSO of either side (Russell & Moore, 2002; Webster, 1983a, 1983b). MSO neurons receive predominantly excitatory inputs from each ear. There are, however, large-scale morphological changes in MSO neurons. MSO neurons have a bipolar morphology with dendrites extending medially and (p. 272) laterally in the brain stem. The medial dendrites receive input from the contralateral CN while the lateral dendrites from the ipsilateral CN (e.g., Figure 13.2A). In response to unilateral hearing loss (right ear, Figure 13.3B), changes occur in the MSO on both sides of the brain stem; the dendrites receiving inputs from the side of the manipulation degenerate while the dendrites receiving input from the normal ear expand (Feng & Rogowski, 1980; Perkin, 1973; Russell & Moore, 1999). There is also evidence that sensorineural losses before the onset of hearing can lead to the growth of novel neural connections between the CN, MNTB, LSO, and MSO (Kitzes, Kageyama, Semple, & Kil, 1995; Russell & Moore, 1995), but this topic is beyond the scope of this chapter (see Moore & King, 2004). Finally, neurons in the IC are also affected by unilateral hearing loss. Neurons in the IC contralateral to the manipulated ear (left side, Figure 13.3B) exhibit shrinkage (Webster, 1983a, 1983b). Such manipulations in adult animals do not result in shrinkage (Webster, 1983b). Moreover, unilateral deafness does not alter synaptic density in the IC on either side in cats (Hardie, Martsi-McClintock, Aitkin, & Shepherd, 1998).

In addition to the changes in neuron size and morphology resulting from unilateral manipulations of the ear, there are also substantial changes in the strength and magnitudes of the afferent projections from one nucleus to another. As reviewed earlier (e.g., Figure 13.2), the IC receives bilateral inputs from all brain stem nuclei, but in a highly asymmetric manner (Figure 13.3A). In normal-hearing animals (e.g., Figure 13.2 and 13.3A), the major afferent projection to the IC from the CN is contralateral with a very small ipsilateral projection (Moore et al., 1989; Nordeen et al., 1983; Oliver, 1987). Neonatal removal of the cochlea changes the CN neuron projections to the IC in dramatic ways. For example, the IC on the side of the unlesioned ear (Figure 13.3B, left side) receives 40% more inputs than normal from the ipsilateral CN (Moore & Kowalchuck, 1988; Nordeen et al., 1983), but the projections to the contralateral IC from the CN of the unlesioned ear remain normal (i.e., Figure 13.3B, left CN to right IC). In contrast, the IC contralateral to the lesioned ear receives 30% less inputs from the CN on the lesioned side (i.e., Figure 13.3B, right CN to left IC). Thus, unilateral cochlear removal in infancy results in a dramatic change in the anatomical balance of inputs to the IC from the CN. There is an increase of inputs to the IC of both sides from the CN on the unlesioned side and a concomitant decrease in the inputs to the IC on both sides from the CN on the lesioned side. Similar results were found in experiments in which a unilateral conductive hearing loss was simulated with ear plugs (Moore et al., 1989). Because unilateral deafness does not alter the synaptic density in IC (Hardie et al., 1998), these results are suggestive of a developing auditory system that competes for a limited and fixed amount of synaptic space in the IC. In terms of the development of the afferent input to the IC, there is a competitive interaction of inputs from the two ears during development, but only for a limited period of time. Cochlear removal after this time period (which is different for the different species studies) does not generally alter this anatomy.

Physiological Changes

The increased magnitude of the projections from the ipsilateral CN to ipsilateral IC following unilateral hearing loss is associated with significant changes in the physiological responses of IC neurons to sounds (Clopon & Silverman, 1977; Kitzes, 1984; Kitzes & Semple, 1985; McAlpine et al, 1997; Silverman & Clopton, 1977). These findings indicate that the observed anatomical changes reviewed above are associated with significant functional changes at the physiological level. After unilateral deafening as neonates, sound-evoked activity in neurons of the IC contralateral to the manipulation (i.e., Figure 13.3B, left IC) in response to sounds presented to the unmanipulated ear (i.e., Figure 13.3B, left ear) increased in adult animals to ~90% of responsive neurons from only ~30% in normal-hearing adults (Kitzes & Semple, 1985; McAlpine et al., 1997; Moore et al., 1993; Nordeen et al., 1983). Moreover, the activity levels of neurons (discharge rates) more than doubled, response thresholds decreased substantially, and the latency to first response decreased (Kitzes, 1984; Kitzes & Semple, 1985). These findings are suggestive of the development of a reduced amount of ipsilateral inhibition from the lesioned side. To test whether these inhibitory inputs were simply “unmasked” by the degeneration of CN neurons by cochlear removal, Moore and Kitzes (1986) lesioned the CN of adult animals. Lesions to the CN did not change the responsiveness of the IC ipsilateral to the intact ear, implying that the changes seen in the developmental experiments were not due to unmasking of inhibitory inputs, but were indeed limited to a developmental sensitive period.

In a very influential series of experiments, rats were raised with a unilateral conductive hearing loss (p. 273) beginning before the onset of hearing (Silverman & Clopton, 1977). The effect of the hearing loss on binaural interaction in neural responses in the IC (Figure 13.2A) was then assessed 3–5 months later. Figure 13.4A shows the Silverman and Clopton data schematically (not actual data). Figure 13.4A illustrates how the IC neurons on the left side responded in normal-hearing rats to monaural sound stimulation of the contralateral ear (right ear, dashed line) and to binaural stimulation of both ears (solid line). When stimulated monaurally, as the sound pressure level (SPL) of the stimulus was increased, the IC neurons increased their discharge rate accordingly. When stimulated binaurally, sounds were presented to both ears and the ILD of the stimulus was varied. Notice that when sounds were presented to both ears, there was a substantial reduction in the discharge rate of the neurons. That is, in the normal-hearing rats, IC neurons are excited by sounds presented to the contralateral (right) ear and inhibited by sounds presented to the ipsilateral (left) ear. This is most apparent at an ILD of 0 dB, where the sound levels at the two ears are identical, in that the responses of IC neurons are largely suppressed. Simply removing the stimulus from the inhibitory ipsilateral ear (i.e., the monaural condition) led to a large increase in neural responsiveness.

In the Silverman and Clopton (1977) experiments, unilateral occlusion in rats during development modified the binaural response properties of IC neurons in dramatic ways. First, the normal ipsilateral suppression of responses present in normal ears (e.g., Figure 13.4A) was largely absent after the deprivation (Figure 13.4B). Note, for example, that the binaural responses with an ILD of 0 dB were equivalent to the monaural responses from the contralateral ear (i.e., no ipsilateral suppression). Moreover, in the IC contralateral to the occlusion, there appeared to be an increase in the strength of inhibition (Figure 13.4C) ipsilaterally from the normal ear. In this case, for a binaural stimulus with an ILD of 0 dB, there was substantially more reduction in the response relative to the monaural contralateral ear than was seen in normal ears. In line with a sensitive period for the development of binaural interaction in the IC, these effects were most pronounced when rats were deprived early in development, and the effect was no longer present if adult rats were deprived (Clopton & Silverman, 1977). Moore and Irvine (1981) reported similar findings in the IC of cats raised with unilateral conductive hearing losses. Finally, both studies attributed the changes in the physiology of IC neurons to central plasticity and not to peripheral changes in auditory sensitivity. In each study, physiological measures of the sensitivity of auditory neurons in the peripheral parts of the manipulated ear (e.g., cochlear microphonic or auditory nerve action potential thresholds) were normal. That is, the method of manipulation did not induce any peripheral sensorineural hearing loss.

These results together reveal that a unilateral conductive hearing loss during some early part of development can lead to substantial anatomical and synaptic reorganization, and this has profound consequences for the physiological responses to binaural stimuli at the level of the IC. These data are strongly consistent with the notion of a competition between converging ipsilateral and contra-lateral inputs to the IC from the two ears during development. The data are consistent with a general downregulation of synaptic activity in the auditory pathways that receive their major afferent input from the ear with the hearing loss. There might also be a compensatory upregulation of synaptic activity in pathways from the normal hearing ear in order to keep the synaptic density, or the overall responsiveness of the neurons, constant (e.g., Hardie et al.,1998). Similar changes in the binaural physiology might be apparent at earlier levels in the auditory pathway, like the MSO, LSO, and their projections to the IC (Figure 13.2), but studies have not yet looked systematically at this.

Behavioral Changes

Development of Sound Localization Mechanisms

Figure 13.4 Functional physiological consequences of unilateral and bilateral auditory deprivation on the responses of neurons in the IC. (A) Normal hearing. Normal auditory pathways (right panel). Recordings from neurons in left IC (right, arrow). For sounds presented monaurally to the ear contralateral (right ear) to the IC being recorded from (left IC), as the sound level was increased the responses of the neurons increased accordingly (dashed line, left panel). When sounds were presented binaurally to both ears and the ILD was varied, the responses of the IC were suppressed relative to the monaural responses (solid line). That is, sounds presented to the ipsilateral ear are inhibitory and sounds to the contralateral ear excitatory, as in Figure 13.2. (B) For animals reared with unilateral conductive hearing loss (X, right ear), neurons in the IC ipsilateral to the loss (right IC) were still responsive to sounds presented monaurally to the normal left ear. But for sounds presented binaurally, the ipsilateral inhibition from the deprived ear (right ear) onto the right IC has been almost completely eliminated as a consequence of the unilateral deprivation. Right panel shows anatomical consequences of the deprivation, as in Figure 13.3. (C) For animals reared with a unilateral conductive hearing loss (right ear), neurons in the IC contralateral to the loss (left IC) respond normally to sounds presented monaurally to the deprived ear (right ear). But for sound presented binaurally, the ipsilateral inhibition from the undeprived ear has been strengthened leading to substantially more suppression of the neural responses relative to normal. Right panel shows anatomical consequences of the deprivation, as in Figure 13.3. (D) For animals reared with bilateral conductive hearing loss (both ears), the responses monaurally and binaurally were essentially the same as normals in A. Right panel shows anatomical consequences of the deprivation, as in Figure 13.3. (Data in left panels based on Silverman and Clopton, 1977.)

Given the obvious importance of the effects of unilateral hearing loss on the development of basic auditory capabilities like sound localization, there is surprisingly very little experimental data on the behavioral deficits that animals reared under these conditions exhibit. In one study, Clements and Kelly (1978) reared guinea pigs with plugs in one or both ears for 11 days after birth and then tested them on a sound localization task for 21 days after that. Guinea pigs are precocial animals whose auditory systems begin to function well before birth. They can make orienting movement to sound sources shortly after birth, suggesting that the binaural circuitry for sound localization is largely in place at birth. Compared to normal animals, animals reared with a unilateral plug and then tested with the plug removed performed extremely poorly (in fact, at chance) and never regained the ability to localize sounds accurately. Knudsen, Esterly, and Knudsen (1984) reported a similar deficit in sound (p. 274) (p. 275) localization in barn owls reared with a unilateral conductive hearing loss, but these animals learned how to compensate for the unilateral loss and regain near-normal localization abilities; similar findings were reported for the ferret (King et al., 2001; King, Parsons, & Moore, 2000). It was speculated that the ferrets learned how to use the monaural spectral shape cues (e.g., Figure 13.1C) to localize sound accurately even though the binaural cues (ILD and ITD) were disrupted during development.

The results from unilateral deprivation during early development are supportive of a “use it or lose it” strategy. If the inputs to an auditory nucleus from one or both ears are not stimulated, they atrophy. And this atrophy has profound implications for the anatomy, physiology, and resultant behavior of the binaural auditory system.

Binaural Deprivation-Balanced and Competitive Interactions

Because bilateral auditory deprivation affects the inputs to the two ears in roughly equal ways (either sensorineural or conductive hearing loss), the central binaural neurons should be equally affected (e.g., neuron shrinkage, death, morphological and synaptic changes, etc.). That is, if “use it or lose it” is the method by which the auditory system develops, then depriving both ears should affect the pathways on both sides in equal ways. However, if a competitive interaction between the inputs from the two ears is necessary for normal development, then occluding both ears should lead to a somewhat “normal” binaural auditory system, since the balance is restored, albeit with less overall input (might only be spontaneous inputs). Unfortunately, there are surprisingly few experimental studies of the effects of binaural deprivation on the development of the anatomy, physiology, and behavior.

Anatomical Changes

As might be expected, rearing animals with bilateral hearing losses leads to the same kinds of anatomical and morphological changes to peripheral auditory nuclei that receive input predominantly from one ear, such as the auditory nerve, CN, and MNTB (Figure 13.3B). But with binaural hearing losses, the changes occur equally on both sides (at least to the extent to which the magnitude of the hearing losses on each side is equal). For example, after bilateral cochlear lesion in infancy, there was near total atrophy of the auditory nerve cells on both sides, and there were also consequent reductions in CN volume (Hardie & Shepherd, 1999; Moore, 1990). Moreover, CN and MNTB neurons were significantly smaller than normal (Webster & Webster, 1977). However, at least one report indicates no significant CN neuron shrinkage after bilateral conductive deprivation (Coleman & O’Connor, 1979). More centrally, while LSO neurons exhibited shrinkage (Webster & Webster, 1977), MSO neurons of binaurally occluded rats had normal dendritic fields, with dendrites projecting equally both medially and laterally (Feng & Rogowski, 1980). Unlike for unilateral loss, where there is IC neuron shrinkage contralateral to the loss (Webster, 1983), after binaural loss, there was no (Webster & Webster, 1979) or minor (Nishiyama, Hardie, & Shepherd, 2000) neuron shrinkage. However, at the synaptic level, bilateral hearing loss in cats initiated near the onset of hearing results in a significant reduction in the number and density of synapses in the IC at adulthood compared to normal animals (Hardie et al., 1998). This latter finding suggests that auditory-evoked inputs are necessary to complete normal levels of synapse development in the central auditory system.

Several studies have also examined the projection patterns from the CN to the IC. Interestingly, bilateral cochlear ablation leads to no quantitative changes in these projections from normal; neither the absolute number nor the bilateral symmetry of the labeled neurons differed significantly from normal adult ferrets (Moore, 1990). Bilateral cochlear removal does not produce the same change in brain stem connections as unilateral removal or unilateral conductive hearing loss. Ferrets with bilateral cochlear lesions just before hearing onset experienced no reduction in the absolute number of IC neurons and the symmetry of the ICs was preserved, just as in normal binaural hearing controls (Moore, 1990).

Studies in the so-called deaf white cat (DWC) have also proven valuable to the investigation of the role of experience in the development of binaural hearing. The DWC has abnormal inner ear structure that causes complete sensorineural deafness at birth, with even a complete lack of spontaneous activity in the auditory nerve (Ryugo, Pongstaporn, Huchton, & Niparko, 1997). The DWC provides an opportunity to study equal binaural deprivation during development. Anatomical studies of the pathways subserving binaural hearing (Figure 13.2) show the binaural deprivation does not alter the normal development of the projection patterns in the brain stem. Early deafness binaurally had no effect on the basic projection patterns seen in (p. 276) normal controls. Congenital binaural deafness in the DWC did not show any significant effects on the connections within the auditory brain stem, and the projections of the LSO and MSO to the IC on both sides were normal. These results are in agreement with those in the ferret by Moore (1990).

Physiological Changes

There are even fewer studies that have examined the physiological consequences of binaural auditory deprivation. The reasons for this lack of data is due to the method of deprivation often used—cochlear ablation. Clearly, without the cochlea, there can be no assessment of the functional consequences of binaural deprivation. However, future research using bilateral cochlear implant stimulation of the two ears (e.g., Smith & Delgutte, 2013) in bilaterally deafened animals could provide valuable information on the plasticity of the developing binaural auditory system and the role of experience. The effects of bilateral conductive hearing losses during development were also examined in the seminal studies of Silverman and Clopton (1977) and Clopton and Silverman (1977). In agreement with the anatomical findings reviewed earlier, Silverman and Clopton (1977) found that binaural deprivation essentially resulted in normal patterns of binaural interaction in IC neurons (e.g., Figure 13.4D). In other words, the pattern of results in the normal rats (Figure 13.4A) was similar to the pattern for bin-aurally deprived rats (Figure 13.4D). These results are in agreement with the competition hypothesis of binaural auditory system development. Even when the input levels at each ear are severely depressed, provided that the inputs are still balanced, then normal anatomy and physiology emerges.

Behavioral Changes

Clements and Kelly (1978) reared guinea pigs with plugs in both ears for 11 days after birth and then tested them on a sound localization task. Animals reared with plugs in both ears performed as good as normal animals. As with the anatomical and physiological studies, these behavioral studies underscore the importance of balanced inputs from the two ears during the sensitive period of development. What seems to matter is not the overall level of the two inputs, but rather whether they are balanced.

Hebbian Processes and the Development of the Binaural Auditory System

In the case of the binaural nuclei of interest here, the MSO, LSO, and IC, it appears that somewhat normal development of the anatomy, physiology, and resultant behavior emerges even after bilateral hearing deprivation during a sensitive period of development. Unilateral deprivation is devastating to the development of the auditory system during the sensitive period. But in the discussions above, there was consideration of only whether there was a balanced amount of neural activity in the two ears. The temporal nature of that activity and whether or not it was correlated at the two ears was not considered. This latter point is important for the following reason: In normal environments, sounds reaching the two ears from any one source will be highly correlated (e.g., Figure 13.1A). As a consequence of this, the evoked neural activity at the two ears will also be highly correlated. One of the most common forms of synaptic plasticity is Hebb’s hypothesis (Hebb, 1949) in which the temporal correlation between presynaptic and postsynaptic neural activity plays a pivotal role in the strengthening or weakening of synaptic contacts. In the binaural auditory system, another kind of Hebbian interaction can be envisioned in which inputs from the two ears onto binaural neurons (MSO, LSO, IC, etc.) are strengthened and maintained when inputs are correlated at the two ears, but reduced or eliminated when they are uncorrelated. There is evidence that this additional developmental mechanism is operating in the binaural auditory pathway.

To test whether correlated inputs from the two ears is an important component of competitive interactions of developmental connections, it is necessary to create an environment where the inputs to the two ears are uncorrelated, but the relative levels of activity remain the same. That is, each ear gets a normal, balanced set of auditory inputs, but the temporal relationships of the inputs are not normal. In one study, Withington-Wray et al. (1990) raised guinea pigs in an environment of so-called omnidirectional white noise. This procedure effectively makes the acoustic inputs to the two ears uncorrelated and unsynchronized, which would result in uncorrelated and unsynchronized neural activity in the two ears. Normally, a single sound source arriving at the two ears results in sound and neural activity that is highly correlated and synchronized, which is critical for the encoding of ITDs. However, such an environment would not necessarily alter the ILD cues. They demonstrated a sensitive period for the development of the so-called auditory space map in the superior colliculus, a multimodal midbrain structure that receives input from the IC. By rearing the animals in this (p. 277) environment at different ages and for different time periods, they concluded that during an approximately 4-day window from P26 to P30, normal auditory experience at both ears was necessary for the normal development of the space map. At this age, the peripheral auditory system, including the brain stem up to the IC, is largely adult-like in its responsiveness to sound. Hence, this result is particular to the development of binaural interactions. This study suggests that in addition to the normal balanced levels of input to the two ears, synchronized acoustic inputs (as would be experienced by sounds arriving at the two ears from a single sound source) are also necessary for the establishment and maintenance of neural structures that are involved in binaural and spatial hearing.

In another series of experiments, gerbils were raised in omnidirectional noise. In normal, binaural hearing adult gerbils, inhibitory inputs to the MSO (a projection not discussed in this chapter) are confined primarily to the soma, while excitatory inputs synapse the distal dendrites. The spatial distribution of glycinergic inputs to the gerbil MSO is initially diffuse and then undergoes a substantial refinement within the first few days after hearing onset. The refinement does not occur if binaural inputs are manipulated during this time by either unilateral or binaural cochlear lesions or raising the animals in omnidirectional noise (Kapfer et al., 2002). Both these manipulations eliminate the correlated inputs to the two ears necessary for binaural hearing based on time differences. Adults in this environment do not exhibit altered glycine distributions. Thus, there is an experience-dependent refinement of synapses from the two ears.

There are also corresponding physiological consequences of this altered experience. Seidl and Grothe (2005) examined the coding of ITDs (see Figures 13.1B,E, and 13.2B), which depend heavily on correlated inputs to the two ears, in the dorsal nucleus of the lateral lemniscus (DNLL). The DNLL is located between the SOC nuclei (MSO and LSO) and the IC, and receives strong inputs from the MSO and LSO. They examined DNLL neurons that presumably received direct inputs predominantly from MSO. In normal animals, no ITD-sensitive neurons were found at P14, but by P15, some neurons were ITD sensitive, but with very low responsiveness (i.e., low discharge rates). ITD sensitivity of neurons in omnidirectional noise-reared animals tested as adults was similar to that of the P15 juveniles, but not adult normals or adults that were exposed to the noise. Data from the noise-reared animals shows that adult-like ITD sensitivity can be suppressed during a sensitive period right after hearing onset and that development of ITD tuning in the gerbil most likely occurs due to plasticity at the level of the ITD detector itself. It is possible that the posthearing onset refinement of glycinergic projections is based on temporal correlations of the naturally produced auditory activity, selectively eliminating inputs that are not contributing properly. These results suggest that the maturation of sound-localization encoding depends on patterned acoustic experience. Experience-dependent plasticity might be necessary for proper ITD tuning and may represent a mechanism of direct adjustment of neuronal processing to behaviorally relevant cues.

The results of binaural deprivation studies, although few, suggest that simple reduction in neural activity might be less detrimental to the development of the binaural circuits for sound localization than unilateral deprivation. At least for the binaural nuclei of interest in this chapter (MSO, LSO, and IC), there appears to be near-normal patterns of development of these binaural circuits. However, normal development of the nuclei that receive bilateral inputs seem to also require correlated acoustical inputs, and thus correlated neural activity, at the two ears. Brain stem development of the representation of both ears appears to start out equal, but is then sculpted and shaped by experience. Balance of inputs is retained in normal binaural hearing, but is substantially altered in monaurally deprived animals. This upsets the competitive balance necessary for normal development. The active ear obtains a competitive advantage and the main anatomical circuits from that ear begin to take over and possibly actively suppress synaptic contacts from the occluded ear. Many of these data, particularly those related to the IC, are consistent with a homeostatic plasticity hypothesis (see Burrone & Murthy, 2003) in which the number and strengths (or gains) of synapses from inputs from the two ears (e.g., CN inputs to the IC as in Figure 13.3A) is adjusted during development to maintain some fixed level of excitability of the neurons.

Evidence of Experience-dependent Plasticity in Human Sound Localization Development

In this section, evidence is considered from human populations that some form of experience-dependent plasticity exists in the development of the human binaural auditory system. A sensitive (p. 278) period for auditory system development is certainly an advantage because it allows for the organism to adapt to its unique acoustic environment. However, plasticity during these periods can also be problematic if the sensory environment is distorted or altered from normal. For example, relatively mild conductive hearing losses in infancy and early childhood may result in communication difficulties when children reach school age. But children whose hearing losses are identified and corrected prior to ~6 months of birth are much more likely to develop better language skills than children whose hearing loss is diagnosed and corrected later (Yoshinaga-Itano, Sedey, Coulter, & Mehl, 1998). Part of this progress is due to normal binaural hearing, since children with even mild unilateral hearing losses (one impaired and one normal hearing ear) also develop poorer language skills and have additional behavioral and educational problems (increased rates of grade failure) than their normal binaural hearing peers (Bess, Dodd-Murphy, & Parker, 1998). This likely occurs because children with unilateral loss require higher speech-to-noise ratios to understand speech in typical settings, like noisy, reverberant classrooms where the ability to hear speech is difficult.

There are many common diseases early in life that alter substantially the normal acoustic inputs to the two ears. In essence, these examples provide naturally occurring “experiments” on the effects of auditory deprivation during development. For example, chronic otitis media (ear infections), otosclerosis, and ear canal atresia all result in varying degrees of conductive hearing loss. Conductive hearing loss results from abnormalities in the outer and/or middle ear that impede the conduction of airborne sound to the inner ear; that is, the sounds that are ultimately transuded into neural impulses in the cochlea are not only attenuated but also delayed in time (Hartley & Moore, 2003). For example, the excessive fluid buildup in the middle ear in otitis media ultimately causes mechanical changes in the coupling of the eardrum to the inner ear, resulting in a conductive hearing loss. This is in contrast to sensorineural hearing loss in which there has been some form of damage or abnormality to the auditory receptors (hair cells), the auditory nerve, or more central parts of the auditory system, which disrupts the normal electrical functioning of the ascending system. There is strong evidence, discussed below, that even temporary hearing loss of any type, conductive or sensorineural, early in life can lead to permanent and wide ranging changes in the structure and function of the auditory system, with profound implications for behavior.

Children who either are born with bilateral or unilateral conductive hearing losses or incur them later (e.g., ear infections) provide important insights into the effects on human development of early deprivation and of uneven competition between the ears for brain stem development. Children with these deficits have been shown to have impairments in basic auditory functions even well after the cause of the conductive loss has passed (e.g., clearing up of ear infection) or surgically corrected and peripheral sensitivity to sound in each ear has returned to normal (Moore, Hutchings, & Meyer, 1991). This is particularly the case for binaural and spatial hearing, where poor performance relative to normal hearing peers may still be detected many years later (Hall & Derlacki, 1986; Hall, Grose, & Pillsbury, 1995; Moore et al., 1991; Pillsbury, Grose, & Hall, 1991). Children who have had higher than normal incidences of otitis media have been shown to often develop deficits in language, reading, and attentional tasks (Zinkus et al. 78). Moreover, children born with otosclerosis (Lucente & Sobol, 1988), ear canal atresia (Wilmington, Gray, & Jahrsdoerfer, 1984), or severe deafness (Beggs & Foreman, 1980) often perform poorly at tasks involving binaural hearing, even well after the problem has been corrected. Because language is often learned in noisy and reverberant acoustic environments, like classrooms, these deficits are believed to be a function of disrupted binaural hearing mechanisms as opposed to a simple attenuation of the sounds, and thus the sensitivity, of each ear (Moore, Hartley, & Hogan, 2003). Indeed, there are physiological correlates of these changes in children with conductive hearing impairment, where they consistently show increased latencies and other abnormalities in binaurally evoked auditory brain stem–evoked responses (Folsom, Weber, & Thompson, 1993; Gunnarson & Finitzo, 1991; Hall & Grose, 1993).

Plasticity is also evident in children born with congenital deafness or deaf children with little or no prior auditory experience. Although research in this area is just now emerging, many of these children have been shown to obtain significant benefit from electrical stimulation of the inner ear via cochlear implants, but only if the device is installed at a relatively young age (Harrison, Gordan, & Mount, 2005; Litovsky et al., 2006). Such results can be at least partially attributed to brain plasticity. The best candidates for cochlear implantation, in terms of outcomes, are very young (p. 279) children and infants or adults who have developed some linguistic skills prior to becoming deaf (Niparko, Cheng, & Francis, 2000; Waltzman, Cohen, & Shapiro, 1991). It is believed that sensory stimulation, whether natural or electrical via the cochlear implant, is necessary during early life to ensure the normal development of the central auditory system. Recent evidence suggests that the human binaural auditory system might be subject to a sensitive period; bilateral electrical stimulation has been shown to be beneficial in adults with post-linguistic onset hearing loss, while those who had little or no auditory experience early in life experience fewer benefits of bilateral cochlear implants (Litovsky et al., 2004, 2006). Clearly, the rationale behind early cochlear implantation is based upon the belief that there is a sensitive period of approximately 4–6 years after birth during which the loss of auditory input is especially detrimental to the development of speech and language abilities (Yoshinaga-Itano et al., 1998), important auditory cortical areas (Harrison et al., 2005; Kral, Tillein, Heid, Hartmann, & Klinke, 2005; Sharma, Dorman, & Kral, 2005), and binaural and spatial hearing (Litovsky et al., 2006). Together, these data support the hypothesis of a sensitive period for the development of binaural hearing in humans and establish this system as a potential model for experience-dependent plasticity.

Acknowledgments

Preparation of this chapter was supported in part by a grant from the NIH-NIDCD (DC006865). I am grateful to the members of my laboratory, Dr. Kanthaiah Koka, Dr. Jeff Tsai, Heath Jones, and Eric Lupo for their comments on and discussions about earlier versions of this chapter.

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