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date: 21 January 2019

Changes in the Inferior Colliculus Associated with Hearing Loss: Noise-Induced Hearing Loss, Age-Related Hearing Loss, Tinnitus and Hyperacusis

Abstract and Keywords

The inferior colliculus is an important auditory relay center that undergoes fundamental changes following hearing loss, whether noise induced (NIHL) or age related (ARHL). These changes may contribute to the induction or maintenance of phenomena such as tinnitus (phantom auditory sensations) and hyperacusis (increased sensitivity to sound). Here, we outline changes that can occur in the inferior colliculus following damage to the periphery and/or as a result of the ageing process, both immediate and long-term, and attempt to disentangle which changes relate to either tinnitus or hyperacusis, as opposed to solely hearing loss. Understanding these changes is ultimately important to reversing the underlying pathology and treating these conditions.

Keywords: inferior colliculus, noise-induced hearing loss, age-related hearing loss, presbycusis, tinnitus, hyperacusis


Trauma to the ear, either by ototoxic drugs or acoustic over-exposure (AOE) or simply as a result of ageing, can result in hearing loss. Age-related hearing loss (ARHL) or presbycusis is the major cause of hearing problems in elderly people. It is usually, but not always, associated with a progressive elevation in hearing thresholds and its prevalence increases with age so that it affects almost two-thirds of adults in their mid-70s (Gopinath et al., 2009). With or without elevation of thresholds, with ageing there can be a deterioration in speech intelligibility, temporal processing, and sound localization (Lee, 2013; Strouse, Ashmead, Ohde, & Grantham, 1998). Many factors may trigger or exacerbate ARHL, including lifetime exposure to environmental noise; exposure to ototoxic agents; or dietary, metabolic, hormonal or vascular changes (Masoro, 1991). There is, however, a considerable genetic component at least of ARHL of cochlear origin, with many genes that either contribute to noise-induced hearing loss (NIHL), promote ARHL, or promote both NIHL and ARHL (e.g., Ohlemiller, 2006). In humans, Schuknecht defined three forms of presbycusis (based on the analysis of human temporal bones) that affect different elements of the transduction process: sensory, neural, and metabolic (Schuknecht, 1955, 1964). A variety of aetiologies of ARHL has been described for different rodent models in the auditory periphery (Fetoni, Picciotti, Paludetti, & Troiani, 2011). In addition, ageing results in other widespread changes in morphology and neurochemistry of the whole brain (e.g., Banay-Schwartz, Lajtha, & Palkovits, 1989; McGeer & McGeer, 1975), and age-related changes have been documented at all stations of auditory processing within the central nervous system from cochlear nucleus to auditory cortex (Caspary, Ling, Turner, & Hughes, 2008).

Hearing loss (as a result of ageing or AOE) is considered the most common trigger for chronic tinnitus, a phantom auditory sensation in the absence of an external stimulus (Eggermont & Roberts, 2004). Tinnitus is extremely widespread, affecting 8–15% of the adult population (Shargorodsky, Curhan, & Farwell, 2010). Historically, the causes of tinnitus were assumed to be within the inner ear, although studies demonstrating its persistence following severance of the auditory nerve or ablation of the cochlea indicated that central auditory system changes must contribute to the phantom percept (House & Brackmann, 1981; Zacharek, Kaltenbach, Mathog, & Zhang, 2002). As an important center for binaural integration from the two ears, as well as a near-obligatory relay for ascending auditory information, the inferior colliculus (IC) has been proposed as a key structure in the generation and maintenance of subjective tinnitus (Robertson, Bester, Vogler, & Mulders, 2012).

Concurrently with the presence of tinnitus, hyperacusis—an oversensitivity to loud sounds—can also occur following cochlear trauma, and tinnitus is comorbid in up to 86% of patients with hyperacusis (Anari, Axelsson, Eliasson, & Magnusson, 1999), findings that suggest common underlying aetiologies. Here, we discuss immediate and early changes in the IC following different types of cochlear trauma and examine pathophysiology in the IC that could underlie hyperacusis. We then examine long-term changes and consider evidence linking these to tinnitus, attempting to identify alterations solely related to hearing loss wherever possible. We also assess how the IC changes as a result of age-related hearing loss (presbycusis). Finally, we discuss how pathological IC activity may be modulated by various interventions.

Noise-Induced Hearing Loss and Its Sequelae

Immediate and Short-Term Changes Following Cochlear Trauma

Here we describe immediate and short-term changes (defined as ≤ 30 days after the insult) that occur in the IC following damage to the cochlea. Spontaneous firing rates (neural activity during silence) appear either unchanged immediately after an acoustic trauma (Dong, Mulders, Rodger, Woo, & Robertson, 2010; Groschel, Ryll, Gotze, Ernst, & Basta, 2014; Wang, Salvi, & Powers, 1996) or even decreased (Niu, Kumaraguru, Wang, & Sun, 2013), but significant increases are usually evident within 12 hours (Mulders & Robertson, 2013). This increase in spontaneous firing is persistent and evident between 1 to 4 weeks later (Hesse et al., 2016; Manzoor, Gao, Licari, & Kaltenbach, 2013; Mulders & Robertson, 2013; Vogler, Robertson, & Mulders, 2014; Wang et al., 2013). Initially, increased spontaneous activity appears to occur over a broad range of frequencies and later narrows to frequencies corresponding to the region of hearing loss (Manzoor et al., 2013; Mulders & Robertson, 2013; Vogler et al., 2014). Such increased spontaneous activity may be caused by a shift in the balance of excitatory and inhibitory inputs to GABAergic and glutamatergic IC neurons observed after noise exposure (Sturm, Zhang-Hooks, Roos, Nguyen, & Kandler, 2017). Similar changes in spontaneous activity are found in recordings from mouse brain slices, but over different time courses—either no change or a reduction in IC spontaneous firing after 1 week, with hyperactivity only apparent 2 weeks after noise exposure (Basta & Ernst, 2005; Groschel et al., 2014). However, it is possible that these differences are a result of the type of recording (in vivo vs. in vitro), as in vivo neural responses may be affected by input from other auditory regions. Certainly, there is evidence that ablation or lesioning of the cochlea or dorsal cochlear nucleus (DCN) can reduce or prevent IC hyperactivity in the early stages of changes following noise exposure (Brozoski, Wisner, Sybert, & Bauer, 2012; Manzoor et al., 2012; Mulders & Robertson, 2009), thereby suggesting a dependence on ascending input.

A number of studies have examined evoked activity following an acoustic insult. Recently, Sheppard et al. (2017) demonstrated that long-term exposure to low-level noise produced enhanced evoked responses immediately after the exposure, despite a reduction in suprathreshold compound action potential (CAP) amplitudes. One week later, IC local field potential amplitudes were enhanced at frequencies corresponding to the noise exposure but suppressed at frequencies above, while CAP amplitudes were also enhanced at this time point. Wang et al. (2002) also demonstrated enhancements in IC responses within 24 hours after noise exposure, at frequencies below the hearing loss, possibly reflecting a decrease in inhibition at these frequencies (as observed in Heeringa & van Dijk, 2016). However, changes in IC-evoked firing rates following noise trauma, as with other changes, may depend on the specific subregion recorded from the central nucleus (CNIC), external nucleus (ICx), or dorsal cortex (ICd). Szczepaniak and Moller (1996b) demonstrated that during exposure to loud tones, generally considered non-traumatic (either 95 dB or 104 dB SPL), click-evoked responses recorded from neurons in the ICx in rats were reduced compared to pre-exposure. However, 15 minutes after exposure, the same responses were significantly larger than baseline recordings, possibly reflecting some degree of hypersensitivity. All such changes could indicate evidence of a neural basis for hyperacusis.

Contrary to these studies, both Popelar et al. (1987) and Sun et al. (2012) demonstrated decreases in IC sound-evoked activity 1 hour following acoustic trauma. Recordings were made from the CNIC in Popelar et al. (1987), while the precise recording location was not specified in Sun et al. (2012), although it is possible that these responses could be restricted to the CNIC. Therefore, extra-lemniscal IC regions, such as the ICx, are likely to exhibit responses different to those from the CNIC following noise exposure. This is perhaps unsurprising, as there are fundamental differences in input between the subregions: the CNIC receives much of its afferent input from the cochlear nucleus, superior olivary complex, and lateral lemniscus, while ICx has many multisensory connections and ICd primarily receives descending input (see Huffman & Henson, 1990).

Corresponding to and probably underlying such functional alterations, there are clear changes in neurotransmission in the short term following cochlear trauma. Extensive evidence indicates that GABAergic inhibition is altered rapidly following noise exposure, which could underlie changes in spontaneous firing rates, although the time courses over which these changes take place vary between studies. Levels of the glutamic acid decarboxylase (GAD) isoform GAD67, the primary enzyme in producing gamma-aminobutyric acid (GABA), were elevated immediately after noise exposure (Abbott, Hughes, Bauer, Salvi, & Caspary, 1999). Two to 30 days later, levels of GAD67 and another isoform, GAD65, were decreased compared to controls. Similarly, Argence et al. (2006) demonstrated that unilateral cochleotomy resulted in a decrease of GAD67 and glycine receptor α1 subunits in contralateral CNIC, starting one day after the procedure and continuing until 8 days later, at which point both measures remained low. Furthermore, Dong et al. (2010) observed that two weeks after noise exposure GABAAα1 subunit expression, which is related to fast inhibitory neurotransmission, decreased in areas of the IC corresponding to frequencies close to the exposure frequency. Complete destruction of the organ of Corti also downregulated GAD67 and GABAtp (another gene associated with inhibitory transmission), although downregulation was also apparent for VGLUT2, which is associated with excitatory neurotransmission (Fyk-Kolodziej et al., 2015). However, there are likely to be significant differences between changes induced by widespread mechanical trauma compared with noise exposure (which is more focused).

All of these studies indicate a net decrease in inhibition following trauma to the periphery. Although Suneja et al. (1998) actually found an increase in GABA release following both cochlear ablation and ossicle removal, this was combined with a decrease in GABA uptake, again suggesting that inhibition was pathologically altered. By contrast, Tan et al. (2007) found an increase in GABA-positive neurons, in conjunction with an elevation in brain-derived neurotrophic factor (BDNF) 6 days after noise exposure, which may be an indication of synaptic plasticity induced by the trauma. Shorter-term increases in BDNF activation were also evident 30 minutes following noise exposure (Meltser & Canlon, 2010), which coincides with an increase in c-fos expression (Saint Marie, Luo, & Ryan, 1999), although here increases in BDNF were no longer significant 24 hours later. Milbrandt et al. (2000) also demonstrated that GAD65 in IC was decreased following noise exposure, both immediately after and 48 hours later, but this completely recovered 30 days post-exposure. However, [3H]muscimol binding was increased at this time point, which is indicative of an increase in GABAA binding sites. Interestingly, Holt et al. (2010) demonstrated that the ICd was the only auditory area with an increase in manganese uptake two days after noise exposure, which is suggestive of increased glutamatergic activity (Takeda, 2003). Therefore, although there is a general consensus that IC neurotransmission is altered following cochlear trauma, there is clearly complexity in how these changes take place.

Long-Term Changes Following Cochlear Trauma

Spontaneous firing rates in the IC remain increased in the long term (> 30 days) following trauma to the cochlea (Berger, Coomber, Wells, Wallace, & Palmer, 2014; Coomber et al., 2014; Longenecker & Galazyuk, 2016; Mulders & Robertson, 2011; Ropp, Tiedemann, Young, & May, 2014; Vogler, Robertson, & Mulders, 2016). Given that evidence of chronic tinnitus-like behavior can take up to 5–8 weeks to emerge (e.g., Turner, Larsen, Hughes, Moechars, & Shore, 2012), this is a time at which it becomes important to differentiate between changes underlying tinnitus compared to those that are simply a result of the noise exposure. Although increases in spontaneous firing rate have classically been considered an underlying contributor to the perception of tinnitus, recent studies, demonstrating no differences between animals with behavioral evidence of tinnitus and those without, raise the possibility that these increases may simply be a product of the hearing loss but not necessarily associated with tinnitus (Coomber et al., 2014; Longenecker & Galazyuk, 2016; Ropp et al., 2014). Furthermore, one recent study demonstrated that repetitive transcranial magnetic stimulation in guinea pigs successfully eliminated behavioral evidence of tinnitus, although IC hyperactivity (increased spontaneous activity) remained unchanged (Mulders, Vooys, Makowiecki, Tang, & Rodger, 2016).

It appears that there is a time-dependent change in the way that increased spontaneous activity is maintained within the IC following noise exposure. Cochlear ablation within 6 weeks can reverse noise-induced hyperactivity (Mulders & Robertson, 2009) but is ineffective beyond this time (Mulders & Robertson, 2011). Furthermore, DCN ablation in the first few weeks following an acoustic insult significantly reduced noise-induced IC hyperactivity (Manzoor et al., 2012). This is supported by evidence indicating that bilateral DCN lesions prior to noise exposure prevented tinnitus-like behavior from emerging (Brozoski et al., 2012), although DCN ablation 3–5 months after acoustic trauma did not reverse preexisting tinnitus-like behavior (Brozoski & Bauer, 2005). However, it is possible that there may still be some dependence on peripheral input at this later stage, as Ropp et al. (2014) demonstrated that IC neurons receiving VCN input were hyperactive 1–4 months following noise exposure, whereas those receiving DCN input were not. Further research is required to determine whether the VCN modulates noise-induced changes in IC activity in the long term. In summary, the evidence just described suggests that IC hyperactivity is generally dependent on ascending input in the short term following noise exposure, but it may later become intrinsic.

There are distinct changes in the firing patterns of IC neurons following long-term recovery from noise exposure. Several weeks after noise exposure, patterns of burst firing emerge, which are associated with increased neural synchrony (Bauer, Turner, Caspary, Myers, & Brozoski, 2008; Coomber et al., 2014). These bursting patterns occur at the same time as a shift in the balance of response profiles, whereby the proportion of IC onset-type responses increases, along with a decrease in sustained responses (Berger et al., 2014), although these were evident regardless of the presence behavioral evidence of tinnitus. Furthermore, noise exposure in juvenile rats can impair sound processing (frequency selectivity) in adulthood: the dynamic range of IC neurons is reduced, inhibitory sidebands are reduced, and excitatory areas are expanded (Bures, Grecova, Popelar, & Syka, 2010; Grecova, Bures, Popelar, Suta, & Syka, 2009).

There is limited evidence for some form of tonotopic reorganization of the IC 1–10 months following noise exposure (Izquierdo, Gutierrez-Conde, Merchan, & Malmierca, 2008), although this reorganization does not occur in the same manner or to the same extent as in the auditory cortex and may simply be a passive process. There is also evidence of changes in IC neurotransmitters which persist following long-term recovery. Three to sixteen weeks following noise trauma, decreases in the density of serotonergic fibers in the CNIC are evident, an effect that is exacerbated in aging mice (Papesh & Hurley, 2012). Given that the neuromodulatory serotonergic system appears to be involved in regulating plasticity, this could reflect plastic changes, underlying alterations in neuronal firing rates, caused by the noise exposure.

Browne et al. (2012) demonstrated that although GAD67 levels were decreased in contralateral IC 4 days after noise exposure, these were at near-normal levels 32 days after. Expression of N-methyl-d-aspartate receptor subunit 2A in the IC, related to excitatory neurotransmission, was decreased at this later time point. Although this seems surprising, given the wealth of evidence showing that firing rates are increased, the authors suggested that reduced excitatory transmission might be to compensate for the hyperactivity. Five months after noise exposure, glutamate and aspartate (related to glutamate synthesis) levels were increased. At that time there was also an unexpected increase in GABA and decreased taurine production, possibly linked to GABA or glycine function (Godfrey et al., 2012). Therefore, while levels of GABA were increased, it is possible that inhibitory function in the IC may have decreased.

Age-Related Changes in the Inferior Colliculus

The standard paradigm for investigating ARHL has been to compare young and old individuals of the same strain. This has been facilitated by using rodent models with shorter lifespans and further by using strains that have accelerated ARHL (see Hazzard & Soban, 1988 for early examples). Most of these models exhibit a progressive hearing loss and this is particularly pronounced in the C57BL/6 strain investigated at the inferior colliculus level by Willott (1986). In this strain, the progressive hearing loss of cochlear origin starts at high-frequency and leads to broader frequency tuning and an enhancement of mid-frequency hearing in the IC, before almost total hearing loss at only 14 months of age. The hearing loss is of cochlear origin in these mice, but there are significant changes in the inferior colliculus of C57BL/6 mice that accompany the hearing loss, which include decrease in the size of principal neurons, reduced numbers of synapses on principal neurons, and a reduction in the area of the soma covered by synapses (Kazee et al., 1995). This very rapid and profound progression of hearing loss is a little extreme compared to other strains (Willott, 1986), and in subsequent work investigators have tended to use other models such as CBA mice or Fischer 344 rats, which do eventually show high-frequency hearing loss but not as early or as profoundly, more in keeping with most human presbycusis. Indeed, the changes in principal cells and synapses, found with ageing in C57BL/6 mice, appear not to occur in CBA mice (Kazee & West, 1999). This suggests that synaptic changes may be a result of the reduced afferent inflow rather than ageing per se. In rats, at least, it is unlikely that presbycusis is mainly associated with changes in the total number of neurons in the IC (Burianova, Ouda, & Syka, 2015).

Despite progressive hearing loss (reaching profound levels) with ageing, the projections from the ventral cochlear nucleus and superior olive to the IC remain stable (Byrd, Frisina, Lynch-Armour, & Walton, 1995; Willott, Pankow, Hunter, & Kordyban, 1985), although one report suggests that inputs from all divisions of the cochlear nucleus to the inferior colliculus decline with age (Lynch-Armour, Frisina, McReynolds, Byrd, & Walton, 1995). Clearly, any ARHL effects that are described at the level of the inferior colliculus can have several elements, some of which may be inherited from lower levels or result from descending influences from higher levels.

Changes to Neurotransmitter Systems with Ageing

As we described earlier, reduced afferent inflow to the inferior colliculus as a result of a variety of causes, including noise overexposure, manifests as significant changes, particularly in the inhibitory (GABAergic) neurotransmission systems. It is not yet known whether changes in the IC with ageing are occurring at this level for the first time or whether they are a consequence of the gradual loss of afferent input as result of age-related changes in the cochlea. However, there are age-related changes in the neurotransmitter systems that occur at the level of the inferior colliculus that may not necessarily reflect peripheral hearing loss, nor appear to simply mirror changes taking place in the rest of the brain. Some morphological changes occur with ageing such as a reorganization of the synaptic endings on the soma and dendrites (Helfert, Sommer, Meeks, Hofstetter, & Hughes, 1999). The exact functional significance of such alterations is unknown, but more obviously functional are a range of different indicators of GABAergic synaptic transmission that have all been shown to change with age. Presynaptically these include a reduction in the number of GABA immunostained neurons (Caspary et al., 1990); reductions in the levels of GABA (Banay-Schwartz et al., 1989; Caspary, Raza, Lawhorn Armour, Pippin, & Arneric, 1990) and in GABA receptor subunits (Gutierrez, Khan, Morris, & De Blas, 1994); reduction in GAD activity (Burianova, Ouda, Profant, & Syka, 2009; Gutierrez et al., 1994); and reduced GABAA and GABAB receptor binding (Milbrandt, Albin, & Caspary, 1994; Milbrandt, Albin, Turgeon & Caspary 1996).

There are also (possibly as a consequence of thepresynaptic changes already described) age-related alterations in the postsynaptic GABA receptor. The GABA receptor consists of pentameric subunit complexes, and with ageing there is a significant downregulation of the α1 subunit and an upregulation of the α3 and γ1 subunits (Caspary et al., 1999; Gutierrez et al., 1994; Milbrandt, Hunter, & Caspary, 1997). Co-expression of various subunits with the γ1 produces an increase in the GABA affinity (Caspary et al., 1999; Milbrandt et al., 1997), which is confirmed by oocyte expression studies and microsac/synapsosome preparations (Caspary et al., 1999; Ducic, Caruncho, Zhu, Vicini, & Costa, 1995). Aquaporin expression changes transiently with ageing in the IC, which may also have an effect on neurotransmitter cycling (Christensen, D'Souza, Zhu, & Frisina, 2009). A combination of all of these factors suggests an age-related reduction in inhibitory function in the inferior colliculus (Caspary, Milbrandt, & Helfert, 1995).

Excitatory neurotransmission in the IC is also altered in ageing. Subunits of the N-methyl-d-aspartate receptor are downregulated and nitric oxide signaling is reduced (Jung, Na, & Huh, 2012; Osumi et al., 2012; Sanchez-Zuriaga, Marti-Gutierrez, De La Cruz, & Peris-Sanchis, 2007). Glutamate related genes are also altered in expression with ageing and hearing loss, leading on the one hand to increased glutamate availability (and possibly toxicity) and, on the other, to an upregulation of a high affinity glutamate transporter that may be compensatory (Tadros et al., 2007).

While the relationship of various calcium-binding proteins to neurotransmission is not fully understood, these proteins are still useful markers of distinct neuronal types and have been shown to change in the ageing IC. Calbindin is present only in the nucleus of the commissure of the inferior colliculus but declines by up to 25% in ageing mice, whereas Calretinin is absent in the central nucleus of the IC but high in the pericentral regions (dorsal cortex and external nucleus), where there was a 40–60% increase in immunoreactivity for calretinin with ageing in CBA mice but not C57 mice (Zettel, Frisina, Haider, & O’Neill, 1997). Parvalbumin (co-expressed in GABAergic neurons) immunoreactivity changes in ageing, but in a strain-dependent manner such that an increase was found in Long Evans rat IC but a decrease in Fischer 344 rat cortex (Ouda, Druga, & Syka, 2008). Parvalbumin is also upregulated in the IC of ageing macaques (Engle, Gray, Turner, Udell, & Recanzone, 2014).

Age-Related Changes in Inferior Colliculus Physiological Responses

Mentioned earlier (Willott, 1986), are changes in responses in the IC in C57BL/6 mice that are consequent on threshold elevations due to peripheral pathology (Fetoni et al., 2011). These changes in frequency responsiveness and tuning affect the tonotopic arrangement in the IC, as also documented using 2-deoxyglucose labelling in rats (Keithley, Lo, & Ryan, 1994). In C57BL/6 mice there was an increase with age in the numbers of spontaneously active neurons, an increase in poorly responsive neurons and pronounced changes in frequency tuning (Willott, Parham, & Hunter, 1988). However, the effect of ageing is, perhaps not surprisingly, species and strain specific (given the different pathologies). In ageing CBA mice, major threshold elevation and changes in tonotopic organization do not occur, with mostly normal activity retained (Walton, Frisina, & O'Neill, 1994; Willott, 1986), although changes in spontaneous rates and the proportion of poorly responsive neurons have been reported (Willott et al., 1988). However, a detailed study of ageing CBA frequency response areas (FRAs; Leong, Barsz, Allen, & Walton, 2011) indicated broader and more symmetric FRAs in middle-aged and old mice, with fewer closed response areas and consequently an increase in monotonic rate level functions. Many of the usual response characteristics can be unchanged in ageing animals: for example in the inferior colliculus of Fischer 344 rats, with only modest threshold elevations of about 30 dB, spontaneous rate, first-spike latency, dynamic range, the proportion of non-monotonic rate level functions, and sensitivity to tone presentation rate show no differences with ageing (Palombi & Caspary, 1996). There were, however, somewhat more subtle changes with ageing in these rats: more units were unresponsive, the maximum discharge rate was lower (by 12%), 12% more units were onset responders, and the iso-intensity functions were 18% wider. Overall, however, neurons in these rats responded to most simple auditory stimuli like those in young animals.

Across a range of studies in different animal models, a consistent finding is that temporal coding measured by a variety of metrics is worse in the ageing inferior colliculus. Fine temporal coding is important for speech recognition and localization, both of which are poorer in elderly individuals (e.g., Gordon-Salant & Fitzgibbons, 1993; Strouse et al., 1998). In particular, the ability to identify gaps in sound is important and this has been the focus of several studies of neural responses in ageing mice. Interestingly, there are neurons in aged CBA mice that have minimal gap detection thresholds of only 1–2 ms, which matches the behaviorally measured ability (Walton, Frisina, Ison, & O'Neill, 1997, Walton, Frisina & Meierhans, 1995). The main difference is, however, that such neurons (which have onset or phasic responses to tone bursts) are much less common in the aged animals (Walton, Frisina, & O'Neill, 1998). In addition, the recovery of the response after the silent gap was generally slower and less complete in neurons from aged animals. A similar increased recovery time has been found using gross potentials such as the auditory brainstem response (Allen, Burkard, Ison, & Walton, 2003) and paired tones (Finlayson, 2002).

Equally important for the discrimination of species-specific vocalizations are fluctuations in amplitude and frequency. Sensitivity to such fluctuations has been studied with sinusoidal amplitude modulated signals and with frequency sweeps. Somewhat surprisingly, although there is a deterioration in sensitivity to the speed of frequency- modulated sweeps in the auditory cortex, this is not evident at the level of the inferior colliculus (Lee, Wallani, & Mendelson, 2002; Mendelson & Lui, 2004). Sensitivity to amplitude modulation in IC is, however, affected by the ageing process. Responses to amplitude modulation are usually quantified using modulation transfer functions (MTFs). These plot either the discharge rate (the rate MTF or rMTF) or the activity locked to the modulation envelope (the temporal MTF or tMTF) as a function of the modulation rate. In young Fischer 344 rats the tMTFs were more commonly band-pass in shape, whereas in older rats the tMTFs were more commonly low-pass in shape, while the proportions of rMTF shapes were similar across the ages, as was the response gain and median maximum discharge rate (Shaddock Palombi, Backoff, & Caspary, 2001).

In aged CBA mice, by using noise carriers the overall response rate to amplitude modulated stimuli was increased by a factor about two and the median upper cut-off frequency of the rMTFs was reduced to about half that in young mice (Walton, Simon, & Frisina, 2002).

In the ageing gerbil there is a decrease in the selectivity to temporally variable pulse trains leading to an increase in signal correlations such that the population response as a whole becomes more homogeneous and less efficient in coding complex sounds (Khouri, Lesica, & Grothe, 2011). A similar result has recently been shown in the auditory cortex of ageing Macaques (Chi-Wing & Recanzone, 2017).

Finally, middle-aged mice C57BL/6J are less able to benefit from spatial separation of signal and masker (McFadden & Willott, 1994) presumably again as a result of the loss of fine temporal coding.

Modulation of Pathological IC Activity

Despite the fact that there is no uniformly effective treatment for either tinnitus or hyperacusis, a number of studies have demonstrated modulation of noise-induced pathological activity related to these conditions in the IC. On the basis that inhibition is suppressed following cochlear trauma, Szczepaniak and Moller (1996a) successfully attenuated noise-induced sound-evoked hyperactivity by systemically administering a GABAB agonist, L-baclofen, to rats. Although L-baclofen, administered at a high dose, also diminished behavioral evidence of tinnitus in rats (Zheng, Vagal, McNamara, Darlington, & Smith, 2012), its efficacy as a treatment in humans is highly variable (Smith, Zheng, & Darlington, 2012), and in some cases it may actually induce tinnitus (Auffret et al., 2014). In a similar scenario, noise-induced hyperactivity in the IC and behavioral evidence of tinnitus have both been suppressed in guinea pigs by acute and chronic administration of the diuretic furosemide (Mulders, Barry, & Robertson, 2014; Mulders, McMahen, & Robertson, 2014). However, once again, although in some patients intravenous administration of furosemide reduced their symptoms of tinnitus (Risey, Guth, & Amedee, 1995), in high doses it may actually cause tinnitus (see Salvi, Lobarinas, & Sun, 2009 for a review).

A phenomenon known as residual inhibition, whereby tinnitus can be temporarily suppressed or eliminated following presentation of a particular auditory stimulus, is evident to some degree in approximately 70% of patients (Roberts, Moffat, & Bosnyak, 2006). Voytenko and Galazyuk (2011) proposed a possible underlying mechanism for residual inhibition, demonstrating that the spontaneous firing of single IC neurons may be suppressed following the presentation of a short stimulus, an effect that was mediated by metabotropic glutamate receptors. Furthermore, Galazyuk et al. (2017) recently demonstrated that this effect is present in approximately 40% of spontaneously active IC neurons, and is similarly evident in animals with behavioral evidence of noise-induced tinnitus, wherein IC neurons were hyperactive. While this method only provides temporary cessation of the phantom percept, it offers a promising tool for examining neuronal states with and without the presence of tinnitus, and further implies a possible role for the IC in the modulation of tinnitus.

A number of studies have examined electrical stimulation of the inferior colliculus as a potential basis for development of an auditory midbrain implant. Offutt et al. (2014) demonstrated that direct electrical stimulation of the ICd resulted in modulation of CNIC firing that persisted after stimulation had ceased, which they proposed as a possible methodology for treating tinnitus. In a follow-up to this study, Smit et al. (2016) found that stimulation of ICx in rats suppressed noise-induced deficits in behavioral gap detection, consistent with the reduction of tinnitus-like behavior. Furthermore, a recent study showed that electrical IC stimulation can result in frequency percepts that correlate with the frequency tuning of the IC (Pages et al., 2016), thus suggesting that this may also be an effective treatment for hearing loss in humans who would not be suitable candidates for cochlear implants. It has also been demonstrated that stimulation of the round window of the cochlea within two-to-three weeks after noise exposure can suppress hyperactivity in IC neurons (Mulders, Spencer, & Robertson, 2016; Norena, Mulders, & Robertson, 2015).

One consideration when examining modulation of noise-induced IC pathology is the time after noise exposure at which interventions are employed. As described earlier, there may be a particular temporal window following a traumatic event, during which time the dependence of the IC on peripheral activity allows treatments that target the cochlea, auditory nerve, or cochlear nucleus to also affect IC activity. However, if IC pathology underlies or contributes to tinnitus or hyperacusis, any treatments targeting the periphery at a later time may not be successful. Clearly, the complexity in the development of tinnitus over time, as well as the uncertainty in differentiating between noise-induced pathology and tinnitus-specific pathology, complicates this process.

Conclusions and Discussion

A finding common to NIHL and ARHL is that there are changes to the machinery of neurotransmitter release in the inferior colliculus. This has been extensively studied for the inhibitory neurotransmitter GABA, and it has been shown that several factors combine to make GABA less available in both NIHL and ARHL. It is somewhat surprising therefore that many studies of ARHL fail to reveal large changes in the physiological response profiles, although other detailed analyses do indeed reveal somewhat subtle changes. Such findings have prompted several authors to suggest that there are compensatory changes occurring in both excitatory and inhibitory neurotransmission (Caspary et al., 1999; Helfert, Sommer, Hughes, Jeffery, & Caspary, 1994; Mendelson & Lui, 2004). In the case of GABA, the presynaptic downregulation and other changes that make GABA less available are offset by a change in the subunit structure, which increases the efficacy of the GABA receptors in transporting chloride ions. In ageing there is also a downregulation in excitatory amino acids such that the balance of excitation and inhibition is less disrupted by the changes in GABA. It is unclear whether changes in neurotransmission due to NIHL and those due to ARHL are both initiated by reduction in afferent activity, since the changes in ARHL appear to occur in some instances without large threshold elevations. A consistent finding, at least in ARHL, is that the temporal coding in the IC is somewhat disrupted, which could provide some basis for the poorer discrimination and speech intelligibility shown by subjects with ARHL.

Hearing loss of cochlear origin that generates a profound high-frequency loss with a sharp frequency transition (beyond an “edge-frequency”) can result in long-term plastic changes in the tonotopic mapping in the auditory cortex (Eggermont & Komiya, 2000; Robertson & Irvine, 1989). This takes the form of a spread of the sensitivity to the edge-frequency across the deafferented cortex. This active reorganization of tonotopy has not been reported in the IC, despite experiments specifically designed to reveal such changes, although some degree of passive reorganization may occur (Irvine, Rajan, & Smith, 2003; Izquierdo et al., 2008).

NIHL has been reported to result in increased spontaneous discharge rates at a variety of levels in the auditory pathway, not least in the inferior colliculus (e.g., Coomber et al., 2014; Mulders & Robertson, 2009; Ropp et al., 2014). This increase has been linked to the changes in neurotransmission suggesting increased “gain” in the processing circuitry (Schaette & McAlpine, 2011). The higher spontaneous rates have been cited as a possible correlate of tinnitus. However, several studies have now shown that such changes in spontaneous rate can be found in all animals that have been subject to damaging levels of noise whether or not there is any behavioral evidence of tinnitus (Coomber et al., 2014; Longenecker & Galazyuk, 2016; Ropp et al., 2014).

Future Directions

Although changes in the IC after NIHL and ARHL seem to correlate in some instances with conditions such as tinnitus, hyperacusis, and presbycusis, it is unclear whether this is merely a correlation or causal. Are other changes taking place (for example, at the auditory cortex) more appropriate mechanisms of tinnitus and hyperacusis and therefore more appropriate targets for intervention? What is it in the ascending input to the IC that is initiating or driving the changes in neurotransmission that eventually become more permanent and independent of peripheral input?

It is known that an enriched auditory environment can alleviate reorganization of auditory cortex caused by severe high-frequency hearing loss (Norena & Eggermont, 2005). It is also clear that enrichment following noise trauma can prevent reorganization of the IC with concomitant alleviation of behavioral indices of pathology (Sturm et al., 2017). It is yet to be determined, however, whether any practical therapy involving acoustic enrichment immediately following acoustic insults will be effective in humans.

Further research is also required to determine whether the VCN modulates noise-induced changes in IC activity in the long term.


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