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date: 21 July 2019

The Cochlear Nucleus as a Generator of Tinnitus-Related Signals

Abstract and Keywords

Tinnitus most commonly begins with alterations of input from the ear resulting from cochlear trauma or overstimulation of the ear. Because the cochlear nucleus is the first processing center in the brain receiving cochlear input, it is the first brainstem station to adjust to this modified input from the cochlea. Research published over the last 30 years demonstrates changes in neural circuitry and activity in the cochlear nucleus that are associated with and may be the origin of the signals that give rise to tinnitus percepts at the cortical level. This chapter summarizes what is known about these disturbances and their relationships to tinnitus. It also summarizes the mechanisms that trigger tinnitus-related disturbances and the anatomical, chemical, neurophysiological, and biophysical defects that underlie them. It concludes by highlighting some major controversies that research findings have generated and discussing the clinical implications the findings have for the future treatment of tinnitus.

Keywords: cochlear nucleus, tinnitus, plasticity, tinnitus-signaling, tinnitus mechanisms, tinnitus origins

As a direct receiver of input from the auditory nerve, the cochlear nucleus is in a pivotal position to respond to the effects of altered input from the ear caused by tinnitus-producing manipulations such as intense sound and ototoxic drug exposure. Alterations of input from the ear caused by these manipulations can manifest as long-term readjustments in circuitry and biophysical properties of neurons, which can disturb the normal state of ongoing activity. As we will see in this chapter, a variety of disturbances relevant to tinnitus have been identified in the cochlear nucleus, and it is the purpose of this chapter to summarize what is known about these disturbances, their relationship to tinnitus, where they originate, and how they affect auditory centers beyond the cochlear nucleus. We will also summarize the current state of knowledge concerning the mechanisms that trigger these tinnitus-related disturbances and the nature of the anatomical, chemical, and biophysical defects that underlie them. Finally, we will discuss some of the major controversies that continue to cloud an understanding of the biological basis of tinnitus as related to the cochlear nucleus and then discuss some of the clinical implications of what is and is not known.

Changes in the Cochlear Nucleus Induced by Agents that Cause Tinnitus in Humans

Historically, the search for neural correlates of tinnitus focused on signals and signal patterns that mimic those evoked by sound. The reasoning was that if a resemblance to sound-evoked activity could be demonstrated, then it seemed likely that such signals carried the necessary information needed to encode the phantom sound percepts that underlie tinnitus. In this section, we will review the key changes in activity that are associated with tinnitus and possess the requisite signatures of sound-encoding signals. We will then examine the evidence supporting the belief that such changes are related to tinnitus.

Changes in Tonotopic Map Representation

Studies of tinnitus signaling in the cochlear nucleus developed as an offshoot of studies of neural plasticity, and particularly in understanding how the tonotopic map was affected by cochlear injury. It was just beginning to be known that the tonotopic map of the auditory cortex underwent a massive reorganization following injury to selected areas of the cochlea, induced by mechanical lesions. Specifically, when a selected frequency region within the cochlea was mechanically lesioned, the corresponding region of the tonotopic map of the auditory cortex neither degenerated nor lost its sensitivity to sound; instead, the tonotopic region affected by the cochlear lesion adopted new frequency tuning properties, expanding the representation of frequencies neighboring those affected by the lesion (Robertson & Irvine, 1989). The reorganized map is thought to have sound encoding potential because the pitch of sound percepts is determined by a “place” code, that is, the tonotopic locus where activity reaches a peak (Evans, 1978). Furthermore, similar changes have been found in the somatosensory cortex after peripheral damage and are believed to underlie phantom pain (Wall et al., 2002). The hypothesis that a similar reorganization might occur at the level of the cochlear nucleus was put to the test in the dorsal cochlear nucleus (DCN), where tonotopy was most easily mapped (Kaltenbach et al., 1996; Meleca et al., 1997). Contrary to expectation, those early studies failed to show any evidence of map reorganization following cochlear injury, such as found in the auditory cortex. Although the map representation included wider than normal areas in which neurons were most sensitive to border frequencies, the tuning properties in the expanded frequency region were all pathological, and the new “ectopic” or expanded frequency selectivity was found to be an artifact of downshifted characteristic frequencies caused by loss of the original tuning curve tip (Kaltenbach et al., 1996; Meleca et al., 1997); this phenomenon was described as a “pseudoplasticity” or “pseudoreorganization” of the tonotopic map (Kaltenbach et al., 1996) and seems unlikely to contribute to the reorganization of the tonotopic map that occurs at the cortical level following cochlear injury (Eggermont, 2006; Komiya & Eggermont, 2000; Norena & Eggermont, 2005; Robertson & Irvine, 1989;).

Increases in Spontaneous Activity (Hyperactivity)

Manipulations that cause tinnitus have been found in many studies to raise the level of resting (spontaneous) activity in the cochlear nucleus. This was originally characterized in the DCN (based on multiunit and single unit recordings) using an intense tone as the inducing manipulation (Brozoski et al., 2002; Kaltenbach & McCaslin, 1996; Kaltenbach et al., 1998, 2000; Zhang & Kaltenbach, 1998), but later studies confirmed that a similar state of hyperactivity can be induced in the anteroventral cochlear nucleus (AVCN) by using intense noise (Vogler et al., 2011) and in the DCN by using the ototoxic drug cisplatin (Kaltenbach et al., 2002; Melamed et al., 2000; Rachel et al., 2002). Studies of the tonotopic distribution pattern of hyperactivity in the DCN originally showed a stereotypic profile of activity that follows a predictable time course: the hyperactivity emerged after several days of plastic readjustment following a period of 2–3 days when activity was reduced or unchanged (Kaltenbach et al., 1998, 2000). This progression is suggestive of a dynamic process, with hyperactivity spread broadly across the entire tonotopic map but gradually becoming more narrowly focused on the frequency region just above the frequency of the exposure sound (Figure 1). Hyperactivity in the DCN following cisplatin treatment was found to be correlated with the loss of outer hair cells (OHCs) (Kaltenbach et al., 2002), suggesting that the hyperactive state may be a secondary adjustment resulting from loss of primary afferent input from the type II spiral ganglion cells, which receive their synaptic input from OHCs. The induction of hyperactivity by manipulations that cause tinnitus has been demonstrated in numerous studies at both single unit and multiunit levels and now appears to be a general phenomenon that can be induced in various species, including hamster (Kaltenbach & Afman, 2000; Manzoor et al., 2012, 2013b), guinea pig (Shore et al., 2008), chinchilla (Brozoski et al., 2002), mouse (Li et al., 2013), and rat (Brozoski et al., 2013; Zhang & Kaltenbach, 1998) by a variety of manipulations that are tinnitus inducing in humans, including sound exposure (Brozoski et al., 2002; Kaltenbach & McCaslin, 1996), ototoxic drug treatment (Kaltenbach et al., 2002; Groschel et al., 2016), and cochlear ablation/eighth nerve deafferentation (Sasaki et al., 1980). Hyperactivity has been found in both dorsal and ventral subdivisions of the cochlear nuclei, although most studies have focused on the DCN. In the DCN, most evidence points to the fusiform cells as the main source of hyperactivity, although, as we shall discuss, some evidence suggests that DCN cartwheel cells may also be involved (Chang et al., 2002; Du et al., 2012). However, the time course of emergence of hyperactivity now appears to vary, depending on the intensity and duration of the inducing exposure sound (Gao et al., 2016). The relationship of hyperactivity to tinnitus will be addressed later in this chapter.

The Cochlear Nucleus as a Generator of Tinnitus-Related SignalsClick to view larger

Figure 1. Intense sound exposure, which is one of the most common and powerful inducers of tinnitus, causes neurons in the DCN to develop hyperactivity. This hyperactivity is shown in this comparison of multiunit recordings from the DCN surface (site marked by X in panel A) of a normal hearing animal (B) with that from an animal that was exposed to an intense (127 dB SPL) 10 kHz tone a month earlier (C). The hyperactivity is apparent as increased spike frequency and amplitude. When this activity is mapped over the DCN surface (D), it shows a distribution pattern that is consistently higher across the tonotopic axis than control levels and shows a distinct peak in the high-frequency half of the tonotopic range (E).

Adapted from Kaltenbach and Godfrey (2008), with permission from the American Speech and Hearing Association (ASHA).

Increased Bursting Activity

Bursting activity is a form of neural discharge pattern in which spikes occur as couplets or in clusters or runs of 3 or more spikes separated by brief (< 10 ms) but similar intervals (Figure 2 B,C). Bursting activity is a characteristic of neuronal signaling at all levels of the auditory system, but its occurrence at the cochlear nucleus level is significant because action potentials concentrated in brief intervals can lead to postsynaptic depolarizations that can be temporally summated; these summated potentials are more powerful drivers of postsynaptic activity in the afferent pathway than are depolarizations that arise from inputs at more widely spaced intervals. Increases in bursting activity also contribute to the increase in firing rate and thus are a major factor underlying hyperactivity (Finlayson & Kaltenbach, 2009). The increases in bursting activity observed in animal models of noise-induced tinnitus have special significance in the context of tinnitus. Bursting activity could increase the salience of percepts. If the bursting activity is concentrated in a specific tonotopic frequency range, the percepts for that frequency range may become more salient. Previous studies showing that increased spontaneous activity is concentrated in the high-pitch region of the DCN (Finlayson & Kaltenbach, 2009) are consistent with this assertion. Bursting activity also promotes long term potentiation, which is widely believed to provide a neuronal substrate for memory (Thomas et al., 1998). Thus, increases in bursting could promote greater sensitivity in the response to ongoing activation, especially if that activation is increased. Finally, since bursting activity contains short interspike intervals, it provides a potential mechanism for representation of high-pitch sounds by periodicity coding (Evans, 1978). Any or all of these properties of bursting could contribute to or reinforce the perceptual impact of sounds arising from the altered activity.

The Cochlear Nucleus as a Generator of Tinnitus-Related SignalsClick to view larger

Figure 2. Bursting activity is increased in the DCN following noise exposure. Non-bursting or “simple” spikes (A) occur as regular or irregular trains of spikes and contrast with bursting activity, which can occur in different forms, including spike couplets (B) and runs (C). Intense sound exposure causes fusiform cells to develop more bursting activity as indicated by the higher prevalence of both spike couplets and runs (D).

Graphs adapted from Finlayson and Kaltenbach (2009).

Evidence that cochlear nucleus neurons develop enhanced bursting activity after noise exposure has been reported in several studies, both in vivo (Finlayson & Kaltenbach, 2009; Wu et al., 2016) and in vitro (Chang et al., 2002; Pilati et al., 2012). Evidence of increased bursting activity of DCN fusiform cells was observed in several ways in the in vivo study of Finlayson and Kaltenbach. The most obvious was an increase in the percentage of units displaying spike bursts (i.e., from 47% in controls to 56% in exposed animals; Figure 2D). Units in exposed animals also showed an increase in the proportion of spikes occurring in bursts (from 20% of spikes in controls to 28% in exposed animals). And lastly, the rate at which bursts occurred was found to be increased in exposed animals relative to those in controls for both couplets and runs. The changes were larger in the Chang et al. in vitro study: doubling of the occurrence of units with bursting activity in the exposed-side-DCN of brain slices from exposed rats.

Increased Neural Synchrony

The term “neural synchrony” refers to the presence of correlated firing such that impulses generated by one neuron occur simultaneously or synchronously with those from one or more other neuron(s). Under normal conditions, most auditory neurons fire in a quasi-random way, and the intervals between spikes are described by a Poisson distribution (Kiang et al., 1965). Stimulation has the effect of increasing the firing rates of neurons, which increases the probability that the different neurons will fire simultaneously. This leads to a shifting of the interval distribution toward shorter intervals, although the pattern of firing may remain similar (Pfeiffer & Kiang, 1965). One would expect that under conditions in which the neuronal firing rate increases as in the animal models of tinnitus, the interval histograms would show a similar tendency to fire with shorter interspike intervals and thus increased synchrony. Increases in synchrony could also be caused by changes in neural circuitry, as proposed by Wu et al. (2016). The reason that an increase in synchrony is important in the context of tinnitus is that synchronous discharges increase the probability that a postsynaptic cell will receive coincident inputs that will drive it to a higher state of depolarization by spatial summation, leading to an increase in its firing rate. Synchronously firing neurons thus have more driving power than asynchronously firing neurons. A second potentially significant feature of synchronous firing is that it could carry a code for sound percepts. This point has been argued previously in the context of tinnitus based on the notion that neurons firing synchronously will be more likely to produce a percept that has salience and therefore stands out above the general background of random activity (Chen & Jastreboff, 1995).

Changes in neural synchrony are often interpreted as putative correlates of tinnitus at cortical and subcortical levels of the auditory system, such as the auditory nerve and auditory cortex (Cazals et al., 1998; see review of Roberts et al., 2010). Increases in the 1 kHz spectral peak of electrocochlear ensemble activity in the absence of acoustic stimulation are induced in the guinea pig auditory nerve after several days of salicylate treatment, and these have been interpreted as evidence for increased synchronous firing across the eighth nerve fiber population (Cazals et al., 1998). Similar increases, although at lower spectral frequency, have also been observed following acute treatment with salicylate in cats by Martin et al. (1993) and Schreiner and Snyder (1987). Only recently has a concerted effort been made to systematically test whether increases in synchrony occur at the cochlear nucleus level. Wu et al. (2016) reported increased synchrony between fusiform cell pairs recorded in the DCN of their guinea pig model of chronic noise-induced tinnitus. Interestingly, the increases were highest in the 12–16 kHz tonotopic range (Figure 3A,B), which correlated with the frequency region over which behavioral evidence for tinnitus was strongest, supporting the hypothesis that the increased synchrony, either alone or in concert with other signal patterns, may represent a neural code for the pitch of tinnitus.

The Cochlear Nucleus as a Generator of Tinnitus-Related SignalsClick to view larger

Figure 3. Synchronous firing between pairs of neurons is increased in animals that have been sound exposed and test positive for tinnitus. The increased synchrony is apparent in a cross correlation histogram (A), which plots the number of spikes that occur in one recorded neuron after a spike is generated in another recorded neuron. As can be seen, there is an increase in the number of spikes occurring at nearly the same time in the sound-exposed animals with tinnitus as compared to the unexposed control animals that do not have tinnitus. This increased synchrony is found across the entire recorded part of the tonotopic range in the exposed animals with tinnitus but reaches a peak between the 12 and 16 kHz loci (B) NE: Non-exposed sham, ENT: Exposed-no tinnitus, ET: Exposed-tinnitus, E-Exposed, Espec: Noise exposure spectrum.

Graphs adapted from Wu et al. (2016), with permission from Elsevier.

Do the Activity Changes in the Cochlear Nucleus Underlie Tinnitus?

The relevance of activity changes in the cochlear nucleus to tinnitus has been studied along two lines of inquiry. The first has examined how these activity changes compare with activity changes induced by sound stimulation, while the second has focused more on the question of whether the activity changes are associated with tinnitus percepts.

Comparison with Stimulus-Driven Activity

As described above, tonotopic mapping studies have revealed that animals treated with tinnitus inducing agents show elevations in spontaneous firing rate with a stereotypical profile characterized by an activity peak in the mid- to high-frequency region of the DCN (Kaltenbach et al., 2000). The activity peak, when averaged across animals, was found to resemble the multiunit activity profile obtained from normal animals responding to a high-frequency tone (Kaltenbach & Afman, 2000). This resemblance suggests that the DCN of tone exposed animals is behaving as though it is signaling the presence of a high pitch sound in the absence of a corresponding stimulus. Based on this tonotopic profile, one might infer that this hyperactive state represents a physiological model of tinnitus, which predicts that animals possessing such hyperactivity might experience tinnitus-like percepts. Much work, which will be discussed further, has been oriented toward the testing of this prediction.

Altered Activity and Tinnitus Percepts

The hypothesis that changes in neural activity are related to tinnitus has been addressed by testing whether animals showing any of the observed changes in activity following treatment with tinnitus inducing agents also show behavioral evidence of tinnitus percepts. Most such studies were modifications of the original test designed by Pawel Jastreboff et al. (1988). Jastreboff’s test yielded results supporting the hypothesis that rats experience acute tinnitus following treatment with sodium salicylate. Jastreboff’s lab also reported that neurons in the inferior colliculus of salicylate-treated rats show elevations of spontaneous firing rates (Jastreboff & Sasaki, 1986) as well as increases in bursting discharge patterns (Chen & Jastreboff, 1995). Subsequently, behavioral studies have reported evidence consistent with tinnitus induction following intense noise exposure in several other species, including hamsters (Heffner & Harrington, 2002), chinchillas (Brozoski et al., 2002), rats (Pace et al., 2016; Zhang et al., 2016), and mice (Middleton et al., 2011; Li et al., 2013). Other studies have shown that the DCN fusiform cells of animals with behavioral evidence of tinnitus exhibit elevated levels of spontaneous activity, bursting activity, and/or synchrony, whereas animals showing little or no behavioral evidence of tinnitus showed little or no increase in these properties (Brozoski et al., 2002; Cacace et al., 2014; Kaltenbach et al., 2004; Li et al., 2013; Luo et al., 2014; Middleton et al., 2011; Wu et al., 2016;.

More recent work has provided further confirmation for the assertion that sound exposure conditions that cause both acute and chronic alterations of spontaneous activity in the DCN also cause animals to experience tinnitus-like percepts. This relationship has been tested with a variety of preparations and methods. Using manganese-enhanced magnetic resonance imaging (MEMRI), several studies have found evidence for increased activation states in both DCN and ventral cochlear nucleus (VCN) of noise-exposed (Brozoski et al., 2007, 2013) or blast-treated rats (Ouyang et al., 2017) that tested positive for tinnitus in behavioral tests. Luo et al. (2014) demonstrated immediate and sustained (up to 1 month) increases of spontaneous activity in the DCN of rats that correlated with behavioral evidence of tinnitus induced by exposure to blast noise. Wu et al. (2016) found that hyperactivity of DCN fusiform cells manifests as both increased spontaneous and sound evoked activity in noise-exposed guinea pigs that showed behavioral evidence of tinnitus based on the gap detection test. Using flavoprotein imaging as a measure of activation levels, Middleton et al., (2011) found evidence for increased resting activity in mice showing behavioral evidence of tinnitus in the gap detection test, while Li et al. (2013), using electrophysiological recordings in vitro, found spontaneous hyperactivity in the DCN of mice testing positive for tinnitus, again using the gap detection test. Most of these studies can be credited for removing the effects of hearing loss on the behavioral test by using animals that developed either no hearing loss or only a temporary hearing loss that recovered by the time the behavioral test was performed. One concern this raises is that they may model a form of tinnitus which is not associated with hearing loss, a condition that is not often found clinically (J. A. Henry, personal communication).

Wu et al (2016) found that the burst rate of DCN fusiform cells, the percentage time bursting activity was displayed, and the degree of synchronous firing by DCN fusiform cells correlated positively with tinnitus behavior, whereas burst duration was negatively correlated with tinnitus behavior.

Imaging Studies in Humans with Tinnitus

Owing to the invasiveness of recording activity from neurons in the human brain, knowledge of activation states in human subjects has come almost entirely from neuroimaging studies. While most of these studies have focused on cortical regions, a few have also examined activity at subcortical levels, and at least three of these have included analysis of the region thought to represent the cochlear nucleus (Lanting et al., 2010; Lockwood et al., 2001; Van Gendt et al., 2012). All three of these studies found increases in activity in the cochlear nucleus of subjects with tinnitus compared with those having no tinnitus. Efforts were made in two of these studies to remove the effects of hearing loss by examining patients with either gaze-evoked or somatically modulatable tinnitus. One of the studies interpreted the region of hyperactivation as representing the DCN (Lockwood et al., 2001). The results are generally consistent with the animal work described earlier showing increased DCN activation associated with tinnitus and somatic modulatability of activity in the DCN (see chapter by Shore, this volume).

Origin of Tinnitus-Related Activity and Its Relationship with Higher-Order Nuclei

Two fundamental issues that impact the significance of cochlear nucleus activity as it relates to tinnitus is where it originates and whether it influences activity elsewhere in the auditory system. The first of these issues concerns the question of whether the activity changes could be derived peripherally from the ear or auditory nerve or centrally from higher levels of the brain. The second concerns the question of whether the activity changes have impact on how neurons function at higher levels of the brain, which could account for the fact that tinnitus is a conscious percept requiring cortical functionality.

Does Tinnitus-Related Activity Originate in the Auditory Periphery?

Although changed activity in the cochlear nucleus results from peripheral damage, several independent lines of evidence suggest that the hyperactivity that develops in the cochlear nuclei after treatment with a tinnitus inducer does not originate in the auditory periphery. Previous studies have shown that acoustic or ototoxic injury to the cochlea results in reductions of spontaneous activity of auditory nerve fibers (Liberman & Dodds, 1984; Liberman & Kiang, 1978; Wang et al., 1997). Diminutions of spontaneous activity are found weeks to months following noise exposure (Liberman & Dodds, 1984). The reductions of activity show a tonotopic profile corresponding to the regions of noise-induced hair cell injury. Decreased activity was found to be maximal in the area with the greatest injury to the tallest row of inner hair cell stereocilia and sloped toward normal levels along the edges of the lesion (Liberman & Dodds, 1984). A second line of evidence is that noise-induced hyperactivity was found to persist in the DCN following both partial and complete ablation of the cochlear partition (Zacharek et al., 2002). These results are consistent with studies in humans reporting that tinnitus often develops secondarily following loss of input to the cochlear nucleus from the ear (Berliner et al., 1992; Fahy et al., 2002; House & Brackmann, 1981; Kameda et al., 2010). These findings converge to support the notion that the increased spontaneous activity of central auditory neurons is a manifestation of reduced or weakened input from the auditory nerve. Thus, deafferentation, whether anatomical or functional, may be one of several important triggers of tinnitus signal generation in the cochlear nuclei. The mechanisms by which this might occur are discussed in a later section. It is worth noting that increases in bursting activity have been observed in the auditory nerve of noise-exposed cats, although this bursting was not associated with increases in spontaneous firing rate (Liberman & Kiang, 1978). The possibility that increased burst firing in the auditory nerve after noise exposure could be relayed centrally and contribute to the increased bursting activity observed in the DCN cannot be ruled out.

Could the Changes in the Cochlear Nucleus Originate from Higher-Order Auditory Stations?

It has been suggested by some investigators that since hyperactivity, increased bursting or increased synchrony are found at the auditory cortical or subcortical forebrain areas of animals treated with tinnitus inducing agents, including noise (Kalappa et al., 2014; Norena & Eggermont, 2006; Seki & Eggermont, 2003;), quinine: (Eggermont & Kenmochi, 1998), or salicylate (Ochi & Eggermont, 1996; Eggermont & Kenmochi, 1998), this may be where the tinnitus-related changes observed in the cochlear nucleus originate. This “top-down” model, however, is inconsistent with the finding that hyperactivity induced in the DCN by noise exposure persists in the DCN even after input from all descending pathways from higher-order auditory centers has been removed (Zhang et al., 2006). This isolation preparation was achieved by transecting all the descending fiber tracts originating from outside the cochlear nucleus, including the dorsal and intermediate acoustic striae and the trapezoid body. This preparation would have removed descending inputs to the cochlear nuclei from the auditory cortex (Meltzer & Ryugo, 2006), inferior colliculus (Andersen et al., 1980; Caicedo & Herbert, 1993; Faye-Lund, 1986; Malmierca et al., 1996; ) and superior olivary complex (Schofield, 2002; Spangler et al., 1987). The hyperactivity that persisted was no weaker than that present when the descending inputs were intact. This would seem to rule out a descending source for the maintenance of hyperactivity in the cochlear nuclei. A role of corticofugal pathways in the maintenance of hyperactivity also seems dubious in light of a study by Imig and Durham (2005), who found that removal of descending cortical input to the cochlear nucleus by surgical decortication produced an increase in metabolic activity of the DCN, indicating release from inhibition. Finally, two imaging studies conducted in human subjects with tinnitus using fMRI found elevated states of activation in the cochlear nucleus and inferior colliculus but not in the auditory cortex (Lanting et al., 2010; Van Gendt et al., 2012). This pattern would seem to contraindicate that the hyperactivity observed in the cochlear nucleus is derived from the cortex. These considerations lead to the view that the cochlear nucleus generates its own state of hyperactivity, independent of inputs from other sources, although it does not rule out the possibility that these changes might also be associated with changes in the level of activity or synaptic function in those descending inputs. As will be discussed later in this chapter and in the chapter by Shore (this volume), there is evidence for such changes in at least two of these descending pathways (the cholinergic system from the superior olivary complex and glutamatergic system from branches of the somatosensory pathway). Changes in descending pathways might be involved in establishing DCN hyperactivity, but they are not needed for maintaining it, as also evidenced by the finding that increased bursting activity and increased sensitivity of acetylcholine receptors occurs in slices of DCN, which have no external connections (Chang et al., 2002).

Do Activity Changes in the Cochlear Nuclei Drive Similar Changes at Higher Levels?

Each of the activity changes just described has counterparts in the inferior colliculus. Hyperactivity, bursting activity, and increased neural synchrony all occur in the inferior colliculus of animals that have been exposed to noise or a tinnitus-inducing drug and/or yielded positive evidence for tinnitus in behavioral tests (Bauer et al., 2008). The hyperactivity that occurs in the IC shows characteristics similar to hyperactivity in the DCN. For example, the peak of the hyperactivity profile occurs in roughly the same high-frequency region of the tonotopic map and follows a similar time course of development as hyperactivity in the DCN (Manzoor et al., 2012, 2013b). In addition, the hyperactivity induced in the IC can be abolished by ablating the contralateral DCN. Also, ablation of the DCN is sufficient to prevent induction of tinnitus in animals (Brozoski et al., 2012). These findings suggest that hyperactivity in the IC is derived from the DCN. A result that raises some question about this conclusion is that ablation of the DCN did not abolish behavioral signs of tinnitus once it was already induced (Brozoski & Bauer, 2005). It could be that hyperactivity in the DCN leads to hyperactivity in the IC, but once the IC hyperactivity has become established, it no longer depends on input from the DCN. This may mean that although the DCN may drive hyperactivity in the IC, the IC may compensate for loss of hyperactive input through homeostatic mechanisms. Further research is needed to clarify this issue

Mechanisms Underlying the Induction of Tinnitus-Related Signal Generation

Efforts to elucidate mechanisms of tinnitus induction have focused on the primary factors that are known to determine the rate and pattern of neural discharges. These include anatomical and chemical changes occurring at the synaptic level and changes that affect the biophysical properties of neurons (i.e., ion channels). Each of these are summarized below.

Synaptopathies

The hypothesis that has received the most attention concerning the mechanism underlying the generation of tinnitus-related activity is that it results from disturbance in the balance of excitation and inhibition. For example, the emergence of hyperactivity is conceptualized as the product of a shift of the balance toward the side of greater excitation, due either to a weakening of inhibition, a strengthening of excitation, or some combination of both. Studies providing support for this concept are reviewed below.

Anatomical changes in excitatory and inhibitory synapses

Anatomical studies bearing on the question of how the balance of excitatory and inhibitory synapses is affected following a tinnitus-inducing manipulation report evidence for degenerative, regenerative, and axonal sprouting (plasticity). Kim et al. (2004) quantified the occurrence of excitatory and inhibitory synapses in the posteroventral cochlear nucleus (PVCN) of chinchillas exposed to intense (108 dB SPL) noise for 3 hours. Synapses were differentiated using classical criteria: those containing pleomorphic (flat) vesicles and symmetrical junctions were interpreted as inhibitory, whereas those containing round vesicles with asymmetrical junctions were interpreted as excitatory. In their noise exposed animals, a progressive decline was found between the first and 24th week after exposure in the total number of both excitatory and inhibitory synapses in the PVCN; much of this decline reflected the loss of auditory nerve input or transneuronal degeneration of neurons in the PVCN. Over a period of a few additional weeks, the recovery was virtually complete for excitatory synapses but incomplete for inhibitory synapses. This was interpreted as evidence of a greater recovery of excitatory than inhibitory synapses, thus favoring a net shift towards stronger excitation, which could correlate with chronic tinnitus but not early onset tinnitus. A similar pattern was also observed on the globular bushy cells of the AVCN. Whether this pattern of recovery also occurs in the DCN was not reported. A later study by Du et al. (2012) found a decrease in immunohistochemically labeled synaptic terminals in the DCN fusiform soma layer of chinchillas 10 days after exposure to intense noise. Electron microscopic study showed evidence of degeneration of terminal endings on cartwheel cells, enlarged and misshaped pleomorphic/flattened vesicles in one of two previously described (Wouterlood & Mugnaini, 1984) synaptic terminal types. These changes occurred only in the middle frequency region of the DCN, which corresponded to the focus of energy in the spectrum of noise used to expose the animals. The investigators interpreted these results as suggesting a reduction of inhibitory input to cartwheel cells. The source of the inhibitory terminals was not identified but could possibly be other cartwheel cells. The authors expressed the possibility that, if so, the disinhibited cartwheel cells may themselves become hyperactive, or alternatively there may also be loss of inhibitory cartwheel cell terminals onto fusiform cells. This latter possibility could account for the increased fusiform cell activity that others have observed following noise exposure.

Chemical changes in inhibitory and excitatory synapses

Effects of cochlear damage on central auditory system chemistry have been recently reviewed (Gold & Bajo, 2014; Lee & Godfrey, 2014), so we will focus on the major changes in the cochlear nucleus that may underlie tinnitus symptoms. In addition to cochlear damage resulting from intense sound and ototoxic drugs, cochlear ablation is among the procedures that are likely to be tinnitus inducing since human subjects often develop tinnitus secondarily following eighth nerve resection (Berliner et al, 1992; Soussi & Otto, 1994; Kameda et al., 2010). Neural pathways that may be involved in the neurotransmitter changes described next are shown schematically in Figure 4.

The Cochlear Nucleus as a Generator of Tinnitus-Related SignalsClick to view larger

Figure 4. Diagrammatic representation of some of the pathways innervating cochlear nucleus neurons via 4 prominent neurotransmitters. Pathways likely using glutamate (purple) are based on Wenthold (1978), Oliver et al. (1983), Osen et al. (1995), Wright & Ryugo (1996), Godfrey et al. (1997, 2015), and Milinkeviciute et al. (2017). Pathways likely using acetylcholine (red) are based on Godfrey et al. (1987, 1990), Godfrey (1993), Vetter et al. (1993), Sherriff & Henderson (1994), and Mellott et al. (2011). Pathways likely using GABA (blue) are based on Davies (1981), Mugnaini (1985), Godfrey et al. (1988), Osen et al. (1990), Potashner et al. (1993), Saint Marie et al. (1993), and Apostolides and Trussell (2013). Pathways likely using glycine (green) are based on Wenthold (1987), Osen et al. (1990), Altschuler et al. (1993), Oertel & Wickesberg (1993), Potashner et al. (1993), Saint Marie et al. (1993), and Oertel and Young (2004). General origins of pathways (colored dots) are indicated, but exact terminations are not included and not always known. Abbreviations: AVCN, anteroventral cochlear nucleus; contraCN, contralateral cochlear nucleus; CunN, cuneate nucleus; DCN, dorsal cochlear nucleus, with molecular (m), fusiform soma (f), and deep (d) layers; IC, inferior colliculus; IN, interstitial nucleus (auditory nerve root); PVCN, posteroventral cochlear nucleus; SOC, superior olivary complex, with also pontomesencephalic tegmentum for acetylcholine; and SpG, spiral ganglion. Green dot in deep DCN represents tuberculoventral cells. Blue dots in molecular layer represent stellate and Golgi cells. Green dot in superficial DCN fusiform soma layer, with smaller blue superimposed, represents cartwheel cells, for which there is evidence for GABA as well as glycine as neurotransmitters.

Reductions in GABA receptor subunit α1 and glutamate decarboxylase messenger RNA expression have been measured in whole cochlear nucleus of guinea pigs a week after partial cochlear damage (Dong et al., 2009). After intense sound exposure, early decreases of these same molecules were followed by increases at 4 weeks survival (Dong et al., 2010), perhaps as a response of the cells to the early depletions. Decreases of GABA levels have been measured in the VCN of rats and chinchillas, although not to any great extent in the DCN, after cochlear ablation (Godfrey et al., 2014, 2015), and in the VCN and superficial DCN after treatment with the ototoxic drug carboplatin (Godfrey et al., 2005), but not after intense sound (Godfrey et al., 2012). Increases in GABA release and uptake were measured in the VCN but not in the DCN after cochlear ablation (Suneja et al., 1998b). After short-term conductive hearing loss, no change in expression of GABAA receptor subunits was found on fusiform cells of the DCN or bushy cells of the VCN (Wang et al., 2011). Overall, since messenger RNA expression does not always correlate well with protein expression (Wang et al., 2009), these results do not provide strong evidence that changes in GABA neurotransmission in the cochlear nucleus, particularly in the DCN, underlie tinnitus symptoms. However, a study on slices from mouse DCN provides evidence for involvement of decreased GABA neurotransmission in the activity of DCN neurons of mice with behavioral evidence of tinnitus (Middleton et al., 2011).

Evidence is stronger for involvement of glycine neurotransmission in DCN hyperactivity. At the whole cochlear nucleus level, a decrease in messenger RNA for glycine receptor subunit α1 was measured a week after partial cochlear damage in guinea pigs (Dong et al., 2009) and, as for GABA, an early decrease followed by increased expression of the same molecule at 4 weeks after intense sound exposure (Dong et al., 2010). Measurements of glycine levels have revealed small decreases in the DCN after cochlear ablation in rats and chinchillas or intense sound exposure in hamsters (Godfrey et al., 2012, 2014, 2015). Increases were measured in the chinchilla DCN after carboplatin treatment (Godfrey et al., 2005), but large decreases in glycine-immunoreactive puncta were measured on several rat cochlear nucleus cell types, including DCN fusiform cells, after treatment with a different ototoxic drug, neomycin (Asako et al., 2005). Decreased glycine release and increased uptake were measured in the guinea pig DCN after cochlear ablation (Suneja et al., 1998b), changes which may reflect decreased glycine neurotransmission. Strong evidence for glycine involvement has come from studies of glycine receptors. In chinchillas, there is evidence that fusiform cells, the major neuron type projecting from the DCN to the inferior colliculus, are sensitive to the actions of the glycine antagonist strychnine (Caspary et al., 1987). Fusiform cells receive some excitatory input from auditory nerve fibers and some from the parallel fiber axons of granule cells, whereas they receive inhibitory input especially from nearby cartwheel cells (Berrebi & Mugnaini, 1991; Godfrey et al., 1997; Mancilla & Manis, 2009; Oertel & Young, 2004; Roberts & Trussell, 2010). The excitatory inputs employ glutamate as neurotransmitter, and the inhibitory inputs primarily use glycine (Oertel & Young, 2004), although GABA may also be involved (Apostolides & Trussell, 2013). A small but statistically significant decrease in glycine receptor binding was measured in guinea pig superficial DCN after cochlear ablation (Suneja et al., 1998a). Decreased expression of glycine receptor α1 subunit protein and decreased strychnine binding, indicative of decreased glycine receptor function, were found in the DCN fusiform cells of rats with behavioral evidence of tinnitus (Wang et al., 2009). Also, high, ototoxic, doses of salicylate have been reported to decrease the frequency of spontaneous inhibitory postsynaptic currents onto fusiform cells in rats, although there was no change in fusiform cell spontaneous activity (Zugaib et al., 2016). Arguing against a strong role of glycine, however, are the results of Middleton et al. (2011) mentioned previously: they did not find much difference in the effects of the glycine antagonist strychnine on DCN activity of mice with behavioral evidence of tinnitus, as compared to control mice. Together, the findings for GABA and glycine would seem to indicate that weakened inhibition of fusiform cells could be an important mechanism contributing to the emergence of hyperactivity in this cell type.

Related to inhibitory neurotransmission is a third amino acid, taurine, which has been found to be associated with GABA and glycine neurotransmission (Albrecht & Schousboe, 2005; Ottersen et al., 1988; Walberg et al., 1990). Taurine can act as an agonist at glycine and both GABAA and GABAB receptors (Albrecht & Schousboe, 2005) and may thereby promote inhibitory synaptic activity. Being also associated with glia (Hassel et al., 1995), taurine levels often increase in regions where nerve fibers are degenerating and gliosis is expected, such as the VCN after cochlear ablation (Godfrey et al., 2014) or treatment with carboplatin (Godfrey et al., 2005). However, after exposure to intense sound, small but consistent decreases in taurine levels were measured throughout the hamster central auditory system (Godfrey et al., 2012), possibly correlating with decreased inhibitory neurotransmission. Taurine is considered to be important in recovery from neural injury (Gupta et al., 2006), and there is evidence that adding it to the diet of rats can decrease behavioral evidence of tinnitus (Brozoski et al., 2010).

From a simpleminded point of view, if increased neural spontaneous activity underlies tinnitus, and decreased inhibitory neurotransmitter function is associated, one might expect an increase in excitatory neurotransmitter function to also possibly be involved. This does not seem to apply for the excitatory amino acids glutamate and aspartate after cochlear ablation or ototoxic drug treatment, since their levels, synthesis, release, uptake, and messenger RNA for AMPA and NMDA receptor subunits fairly consistently decrease in the cochlear nucleus following these manipulations (Dong et al., 2009; Godfrey et al., 2012, 2014, 2015; Potashner et al., 1997; Wenthold, 1978; Zeng et al., 2009). However, following intense sound exposure, after initial decreases, increases in messenger RNA for AMPA and NMDA receptor subunits were measured at 4 weeks survival for whole guinea pig cochlear nucleus (Dong et al., 2010), and many increases in glutamate AMPA-type receptor expression were measured in the chinchilla VCN, although not in the DCN, after noise trauma (Muly et al., 2004). Increased D-aspartate release and decreased uptake have also been reported in both VCN and DCN of chinchillas after noise trauma (Muly et al., 2004), changes that may be associated with increased excitatory neurotransmission. At 5 months after intense sound exposure, small but consistent increases in glutamate concentration were found throughout the hamster cochlear nucleus and larger increases for aspartate (Godfrey et al., 2012). Although evidence for a neurotransmitter function of aspartate is much less than for glutamate, the two amino acids are closely linked metabolically (Ross et al., 1995), so that increases in aspartate concentration could easily contribute to increased excitatory neurotransmission by increasing the supply of glutamate.

Most acetylcholine neurotransmission in the cochlear nucleus has been associated with centrifugal pathways to its various parts (Godfrey, 1985; Mellott et al., 2011). Acetylcholine can serve as either an excitatory or inhibitory neurotransmitter, depending on the nature of the postsynaptic channels at a particular synapse (Moises & Womble, 1995). In the cochlear nucleus, early in vivo studies found mainly excitatory effects of acetylcholine in the VCN and inhibitory effects in the DCN (Comis, 1970; Martin & Adams, 1979; Caspary et al., 1983; Godfrey, 1985), but more recent in vitro studies found predominantly excitatory muscarinic acetylcholine effects in the rat DCN (Chen et al., 1994, 1995). Cochlear ablation results in short-term increases in activity of the synthetic enzyme for acetylcholine, choline acetyltransferase, throughout the rat cochlear nucleus, but most of these increases are no longer present at 2 months after the lesion (Jin et al., 2005). Binding to muscarinic acetylcholine receptors also increases after cochlear ablation throughout the rat cochlear nucleus except for the DCN molecular layer, and continues to increase through 2 months after the lesion (Jin & Godfrey, 2006). After intense sound exposure, choline acetyltransferase activity increased in most hamster cochlear nucleus regions through 2 months after exposure (Jin et al., 2006), but the increase was sustained through 5 months only in the granular region adjacent to the AVCN (Godfrey et al., 2013). These results suggest an increase in acetylcholine function in the cochlear nucleus after types of cochlear damage that may result in tinnitus, especially in granular regions. Granule cells themselves do not appear to use acetylcholine as neurotransmitter, but they receive innervation that uses acetylcholine (Köszeghy et al., 2012), and themselves use glutamate as transmitter (Chen et al., 1999; Godfrey et al., 1997). Their axons mostly or entirely project to the superficial layers of the DCN to synapse on the dendrites of cartwheel and fusiform cells (Berrebi & Mugnaini, 1991; Godfrey et al., 1997; Mugnaini et al., 1980; Osen, 1988; Wouterlood and Mugnaini, 1984). There is evidence that, besides granule cells, cartwheel cells of mice have muscarinic acetylcholine receptors that affect glutamate neurotransmission from granule cells onto them (He et al., 2014) and that fusiform cells of rats also have such receptors (Chen et al., 1994, 1995; Pál et al., 2009). In addition, Golgi cells, which provide inhibitory input to granule cells, were hyperpolarized via muscarinic acetylcholine receptors in slices of mouse DCN (Irie et al., 2006), which could result in increased granule cell activity. A recent study reported that blocking muscarinic acetylcholine receptors affected spontaneous activity and stimulus timing-dependent plasticity in fusiform cells of guinea pigs (Stefanescu & Shore, 2017). These effects on long-term synaptic plasticity may be mediated through endocannabinoid signaling (Zhao & Tzounopoulos, 2011). After intense tone exposure in rats, increased sensitivity to the non-selective acetylcholine agonist carbachol was found among bursting neurons, which could be cartwheel cells, or fusiform cells that had changed their firing patterns, or both, in the DCN of rat brain slices (Chang et al., 2002). As already mentioned, cartwheel cells provide inhibitory, glycinergic/GABAergic input to fusiform cells (Oertel & Young, 2004; Apostolides & Trussell, 2013), as well as to other cartwheel cells (Mancilla & Manis, 2009; Roberts & Trussell, 2010). On the other hand, an in vivo study found that the hyperactivity measured in hamsters previously exposed to an intense tone could be decreased by application of carbachol to the DCN (Manzoor et al., 2013b).

It is difficult to combine all the data on neurotransmitter-related changes following cochlear damage that may lead to tinnitus into a comprehensive understanding of what changes may underlie the tinnitus symptoms. This is partly because of the variety of animal models used in the studies, sometimes giving conflicting results, partly because of different survival times used in the various studies, which may only sample one or a few time points during the progression of changes that may underlie tinnitus, and partly because the various studies have measured only certain aspects of neurotransmitter chemistry. However, available data suggest that there may be an increase in acetylcholine function, mediated through muscarinic receptors in the granule cell—cartwheel cell—fusiform cell system, combined with increased excitation mediated by glutamate, and some decreased function of cartwheel cells and their inhibitory glycinergic (and possibly also GABAergic) neurotransmission onto fusiform cells. This could result in increased spontaneous activity of fusiform cells, because of direct cholinergic activation and increased granule cell activation, together with decreased cartwheel cell inhibition. If this is the case, then the suppression of DCN hyperactivity by application of 100 µM of the acetylcholine agonist carbachol to the DCN surface (Manzoor et al., 2013a) may result from a general delayed suppression of the circuitry by this high dose, such as by a long term depression mechanism. Alternatively, in view of the variety of neurotransmitter-related changes after cochlear damage, tinnitus may be a manifestation of any imbalance among neural activities in the central auditory system that may result from changes in the various neurotransmitter functions.

Channelopathies

The concept that tinnitus signal generation might arise as a result of changes in the intrinsic membrane properties of neurons is relatively more recent than the synaptopathy concept. The channelopathy theory is simple and intuitively appealing because ion channels largely control the base level of excitability of a cell, by changing the thresholds for action potential generation, the durations of action potentials, and/or the recovery times (refractory periods) following action potentials. The distribution and numbers of expressed ion channels in the somatic or dendritic membranes also determine the properties of spatial and temporal integration. All of these factors determine the rates and patterns of neuronal impulse generation, and thus a change in any of these features is a potential mechanism of tinnitus related activity. In practice, it is to some extent arbitrary to draw a line of separation between changes in neurotransmitter receptor expression and changes in ion channel expression as independent categories, since many receptors function as ligand gated ion channels. Therefore, to differentiate this category from those of a more synaptic nature, the present subsection will examine only changes in channels that are not synaptic receptor channels (ionotropic). These include the voltage-gated ion channels and the non-voltage-gated ion channels and are discussed separately.

Changes in voltage-gated ion channels

Much less is known about the role of ion channels in tinnitus compared to synaptic anatomy and chemistry, and only a few studies concern the cochlear nucleus. The first hints of altered ion channel conductances were obtained from studies of brain slices of mice examined 2 weeks following bilateral cochlear ablations (Francis & Manis, 2000). Cells in the VCN showed smaller action potentials, more depolarization, and smaller afterhyperpolarizations with shorter membrane time constants compared to cells from unablated control mice. Some cells also showed evidence of increased input resistance.

Direct evidence for altered ion conductance that seems likely to be related to tinnitus has recently been reported by Pilati et al. (2012). They observed a decrease in high-voltage-activated (HVA) potassium currents in DCN fusiform cells exposed to intense sound 3–4 days earlier. This decrease was found to correlate with a shift from regular to burst firing (complex or irregular spiking) and longer duration action potentials of fusiform cells. Since increases in bursting activity were previously shown to contribute to the increase in overall discharge rate of fusiform cells (Finlayson & Kaltenbach, 2009), the findings of Pilati et al. may provide a mechanism underlying hyperactivity, with decreased HVA potassium conductances contributing to slower repolarization following action potential generation and the emergence of bursting activity.

Li et al. (2013) measured KCNQ2/3 (M) currents in DCN fusiform cells to investigate the role of Kv7.2/3 (KCNQ) channels as a possible substrate of noise-induced tinnitus. KCNQ channels function as brakes on action potential generation and therefore control the excitability of neurons (Delmas & Brown, 2005; Soldovieri et al., 2011). Decreases in their expression lead to hyperexcitability disorders such as epilepsy (Soldovieri et al., 2011). In the study by Li et al., KCNQ currents were found to be reduced in DCN fusiform cells of mice immediately after they tested positive for tinnitus 1 week after noise exposure. Such reductions were not found in unexposed control mice or in noise-exposed mice testing negative for tinnitus. The reduced KCNQ currents were observed in the hyperactive high-frequency half of the DCN, but not in the low frequency half, which was not hyperactive. Animals that had been pretreated with the anti-epileptic drug and KCNQ blocker, retigabine, did not show tinnitus, nor did they exhibit hyperactivity in the DCN. The authors inferred from their findings that KCNQ channel reduction is essential for the induction of tinnitus and tinnitus-related hyperactivity in the DCN following noise exposure. This reduced channel conductance could induce hyperactivity by shifting the voltage dependence of the channel to more positive voltages, pushing the cell closer to the threshold for action potential generation. Although retigabine has a number of serious side effects which limit its usefulness as a therapeutic agent, a more recent study has shown that a less toxic drug that also blocks KCNQ channels has a similar effect as retigabine on tinnitus and tinnitus-associated hyperactivity (Kalappa et al., 2015).

Non-voltage/non-ligand-gated ion channels

In the cochlear nucleus, changes in the expression/conductivity have also been observed in the two-pore-domain potassium channels (K2PD) as well as in the expression of the inward-rectifier potassium channels. K2PD channels are involved in setting resting membrane potentials via their role in regulating potassium ion leakage. These channels thus participate in the control of neuronal excitability. Holt and colleagues (2006) reported that decreases occur in the expression of multiple subunits of the K2PD channel in the cochlear nucleus of rats following bilateral cochlear ablation. The timing of the decreases varied with subunits: some decreases occurred between 3 days and 3 months, while others were decreased only at the beginning or end of this post-ablation range. Since the decreases were found in whole cochlear nucleus homogenates, future studies will be required to pin down the distribution and degree of change in this channel in specific subdivisions. Nonetheless, the available results do suggest another potential mechanism that could contribute to the hyperactive state underlying tinnitus, since reductions in this channel’s expression would be expected to become manifest as a decrease in potassium leakage, thus shifting the potential in the positive direction and making the cell more excitable.

Issues, Challenges, and Controversies

As the foregoing narrative has summarized, the concept that the cochlear nucleus plays a key role in the generation of tinnitus-related signals is supported by a substantial body of evidence. However, like many other concepts in neuroscience, this concept is complex and has elements that remain unclear or even controversial. Next we highlight the main issues that are most uncertain and provoke the most discussion and controversy:

  1. 1. The neural correlate of tinnitus. Although the three abnormal states of activity (hyperactivity, increased bursting, increased neural synchrony) that are associated with tinnitus have the hallmarks of sound encoding signals in terms of tonotopicity and timing (see previous discussion), it remains unclear which of these is necessary and sufficient for the generation of tinnitus percepts. Whether tinnitus is the product of one of these or instead results from a combination of these signals is an issue that needs further clarification.

  2. 2. The trigger of tinnitus activity induction. An issue that needs further elucidation is the precise change that triggers induction of the abnormal states of activity in the cochlear nuclei. What is the relative importance of inner versus outer hair cell injury? Injury to either type of hair cell has been reported to trigger tinnitus related changes in activity in central auditory nuclei (Bauer et al., 2008; Kaltenbach et al., 2002), but there is also evidence that chronic increases in spontaneous activity and tinnitus can be induced by moderate sound exposure conditions (80 dB SPL) that do not cause chronic hearing loss and would seem to be below the intensity level needed to permanently damage either inner or outer hair cells (Brozoski et al., 2002; Kaltenbach et al., 2005). Thus, the common view that the abnormal activity is triggered by deafferentation caused by injury to the cochlea may be too simplistic. Indeed, recent evidence suggests that tinnitus related activity may be induced by other triggers such as activity-dependent (e.g., LTP/LTD) (Stefanescu & Shore, 2017) or homeostatic plasticity (Schaette & Kempter, 2006) and/or excitotoxic injury (Criddle et al., 2018), but the issue of the relative importance of each of these remains obscure. Perhaps all contribute to some degree as part of a complex equation of interacting factors.

  3. 3. Mechanism of tinnitus signal induction. Further work is needed to clarify the precise mechanism leading to these abnormal states. As we have described, both synaptic and non-synaptic mechanisms have received experimental support for a contributory role from careful in-depth studies, but more research is needed to determine which is more critical to the emergence of signals that are tinnitus producing.

  4. 4. The role of descending pathways. The role of upregulation of descending inputs (Godfrey et al., 2013; Lee & Godfrey, 2014) to the cochlear nucleus is unclear. It is possible that this up-regulation reflects a compensatory increase in central gain caused by the loss of normal input from the ear. This possibility is difficult to reconcile with the finding that hyperactivity persists in the cochlear nucleus even after all descending inputs from higher-order auditory nuclei have been removed, but the effects of descending pathway terminals may persist for several hours after their axons have been cut (Chen et al., 1998), longer than the post-surgery time in the Zhang et al. (2006) study. Perhaps the effects of the descending inputs are decreased as a secondary consequence of diminished input from the ear. Alternatively, upregulated inputs from descending pathways may play a role in triggering the induction of abnormal activity in the cochlear nucleus but may not be required for its maintenance. Yet another possibility is that the upregulation of the descending cholinergic system to the cochlear nucleus might also be an attempt by the CNS to compensate for or suppress the hyperactivity that develops in the cochlear nucleus after noise exposure.

  5. 5. The role of dorsal versus ventral cochlear nuclei. The relative roles of the dorsal and ventral subdivisions of the cochlear nucleus in driving activation states at higher levels of the auditory pathway where tinnitus-related signals are translated and interpreted as tinnitus percepts needs to be clarified. While fusiform cells in the DCN have been shown to be important, other studies suggest that cartwheel cells might also become hyperactive after noise exposure and that changes occur also in the VCN. Increased cartwheel cell activity needs to be reconciled with the hyperactivation of fusiform cells as a driver of hyperactivity in the inferior colliculus, since cartwheel cells are inhibitory to fusiform cells.

  6. 6. Lastly, the link between these changes and the intracellular processes governing gene and protein expression that determine the level and pattern of firing by neurons has yet to be characterized.

In conclusion, while tinnitus research has provided a skeletal framework for understanding the early stages of tinnitus signal generation, many questions at the cellular, molecular and circuit levels remain to be clarified. It seems that the problems have reached a level of complexity that will require an extraordinary level of sophistication and coordination of complementary approaches and experimental design to clarify or resolve these issues. More pooling of resources and cooperation among laboratories may be needed than has been typical in the past.

Clinical Implications of Our Current Understanding of Tinnitus-Generating Mechanisms

The mechanisms of tinnitus generation are very complex, and the ability to treat this disorder will depend not only on knowledge of the locus and mechanisms of the underlying defects, but also on an ability to successfully correct those defects without producing untoward side effects. This is complicated by the fact that the receptors and ion channels that become disturbed in tinnitus are shared by numerous other cell populations, many of which are located in parts of the brain that control or affect vital functions. The ability to successfully target the tinnitus defects without disturbing those other functions is likely to be a challenge, but there are reasons to be optimistic that this goal is achievable. First, the brainstem auditory nuclei normally have high levels of spontaneous activity relative to other areas of the brain (Kilduff et al., 1982). If the elevations of activity that result in tinnitus generation push the activation state outside the range of activation of nuclei that underlie vital functions, this opens up the possibility that the cells that generate tinnitus signals would be more likely to respond to a drug with greater sensitivity than those that have lower states of activation. Second, recent studies have succeeded in demonstrating suppression of noise-induced hyperactivity in the DCN and IC using the Kv3 channel modulator, AUT00063. The suppression effects were achieved without affecting response thresholds and without affecting at least two vital functions (heart rate and breathing rate). Third, a recent study by Kalappa et al. (2015) reports development of a new drug, SF0034, that blocks KCNQ channels without causing severe side effects. When mice were pretreated with this drug before being exposed to intense noise, the mice did not develop hyperactivity in DCN fusiform cells and showed no behavioral signs of tinnitus after the noise exposure. Fourth, there are promising signs that cochlear nucleus stimulation using electrodes placed in or on the DCN results in suppression of tinnitus, both in rats and humans (Luo et al., 2012; Soussi & Otto, 1994; Behr et al., 2007; Roberts et al., 2017). And fifth, tinnitus loudness can be reduced in humans by applying electrical stimulus trains that are known to induce long term depression of DCN fusiform cells in animals. These are promising signs that the understanding of the role of the cochlear nucleus as a tinnitus generator site have begun to yield translational applications that may eventually prove to be the stepping stones to more effective anti-tinnitus therapies.

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