Neural Plasticity
Volume 2016 (2016), Article ID 2162105, 9 pages
http://dx.doi.org/10.1155/2016/2162105

Review Article

Neural Hyperactivity of the Central Auditory System in Response to Peripheral Damage

Yi Zhao, Qiang Song, Xinyi Li, and Chunyan Li

Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China

Received 28 August 2015; Revised 12 November 2015; Accepted 15 November 2015

Academic Editor: Aage R. Moller

Copyright © 2016 Yi Zhao et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

It is increasingly appreciated that cochlear pathology is accompanied by adaptive responses in the central auditory system. The cause of cochlear pathology varies widely, and it seems that few commonalities can be drawn. In fact, despite intricate internal neuroplasticity and diverse external symptoms, several classical injury models provide a feasible path to locate responses to different peripheral cochlear lesions. In these cases, hair cell damage may lead to considerable hyperactivity in the central auditory pathways, mediated by a reduction in inhibition, which may underlie some clinical symptoms associated with hearing loss, such as tinnitus. Homeostatic plasticity, the most discussed and acknowledged mechanism in recent years, is most likely responsible for excited central activity following cochlear damage.

1. Introduction

The mammalian auditory system falls broadly into two pieces, the auditory periphery and the central auditory system. The auditory periphery, which comprises the sound receptors, performs an acoustoelectric transformation. The electrical signals are then sent to the central auditory system for further processing, and eventually, the sensation of sound occurs. In pathological conditions, hearing impairment usually develops as a result of receptor dysfunction. For example, the great majority of acquired sensorineural hearing loss is caused by damage to hair cells in the cochlea. Risk factors for this kind of hearing loss include administration of ototoxic drugs, aging, and overexposure to noise. In fact, among the various manifestations of hearing pathologies confined to the auditory periphery, hearing loss is the most common one.

Pathology of the cochlea as a cause of hearing loss has been investigated comprehensively in recent years. However, the role of the central auditory system in hearing loss is still not fully understood. Except in rare cases where the brain and cochlea are both impaired by certain agents, brain changes are considered to be a response to an altered input from cochlea, rather than being directly caused by chemical or environmental factors. These neural changes in the central auditory system, that is, auditory neuroplasticity, have been observed in a broad range of brain behaviors during development and maturation [1–3]. Auditory neuroplasticity can also be observed after hearing loss as a kind of reactive adaption [4]. One of the most common topics of focus in this field concerns the mechanism(s) of tinnitus, that is, perception of sound in the absence of any stimulus, a condition that may develop following sensorineural damage to the auditory structures. Because tinnitus is often associated with a variety of hearing pathologies, attention has been paid to the link between them.

It has long been appreciated that tinnitus appears to persist in the patients diagnosed with acoustic neuroma and in cases where the auditory nerve is transected. Indeed, recent animal experiments have confirmed this by showing an overexcited state in the auditory brainstem after acoustic overstimulation, regarded as a behavioral sign of tinnitus [5, 6]. However, tinnitus has also been found independent of cochlear activity [7, 8]. Although little consensus has been achieved, it is considered that neural plasticity plays a critical role in development of tinnitus [9, 10].

The aim of this review is to assess how peripheral pathologies are associated with different damage agents and especially how pathologies of sensory cells influence neurons in the central auditory pathways. Responses to different damage agents are compared, and some commonalities and correlations among various hearing pathologies are discussed.

2. Influence of the Cochlea as a Whole

2.1. Cochlear Ablation

Important parallels have been drawn between this topic and the current state of research on neuroplasticity in the visual system. Vision and hearing are two major human sensations and share many similar structures and functions. Visual deprivation brings about changes in response properties of neurons in the visual circuits. For example, when one eye is covered, the spiking responses of visual cortical neurons are shifted in favor of the untreated eye, and visual acuity in the blocked eye is reduced [11–13]. Central auditory pathways may also be subject to modification as a result of alterations in peripheral input, as in the visual system. The general consequences of cochlear removal include degeneration of auditory nuclei in the brainstem [14, 15] and reorganization of axonal connectivity between the nuclei [16, 17]. Moreover, cochlear ablation may also result in various cellular and molecular changes, including those in gene expression, synaptic activity, and protein synthesis. For example, upregulation of growth associated protein- (GAP-) 43 and synaptophysin seems to indicate that neural circuits are subject to synaptic reorganization [18–20]. At the same time, some neurotrophins, such as insulin-like growth factor 1, have been identified that may contribute to synaptogenesis [19, 21]. All of these changes may contribute directly or indirectly to altered auditory pathway activity.

Several studies have demonstrated that unilateral cochlear ablation can enhance the responsiveness of neurons in the central auditory system. In cochlea-ablated neonatal gerbils, stimulation to the nonoperated side resulted in lower response thresholds, greater peak discharge rates, and reduced minimum response latency in inferior colliculus (IC) neurons, despite response patterns comparable to those of normal animals [22]. These changes are consistent with an increased proportion of excited neurons in the IC [23–25]. Measured with whole-cell voltage-clamp recordings in brain slices, the amplitude and duration of evoked excitatory postsynaptic currents (EPSCs) increased significantly, combined with a decrease in inhibitory postsynaptic current (IPSC) conductance and a depolarization of the IPSC reversal potential [26]. Similar electrophysiological results in the auditory cortex (AC) confirmed increased excitation after cochlear ablation [27, 28]. The mechanism underlying this enhanced performance was hypothesized to be a loss or downregulation of inhibitory influence [24]. Based on the time course of events, Mossop et al. [24] suggested two possible causes of the altered central response. First, functional unmasking, a stimulus-related phenomenon, may lead to an increase in responsiveness within minutes or hours. Deactivation of surrounding inhibitory circuits, which are normally used to suppress the response of the auditory pathway, intensifies excitatory inputs and increases overall responsiveness. Another possibility involves a delayed reduction in neurotransmitter-mediated inhibition. For example, GABAergic-associated events may be decreased, which may help explain long-term changes. The expression of GABA receptors and the level of GABA synthetase are both greatly compromised after cochlear ablation [24, 29]. Furthermore, GABA release was found to be elevated for a couple of days, but then it dropped over the long term. Moreover, the results varied to some extent at the lower levels of the brainstem [30]. This may indicate that changes in transmitters occur in a complex, dynamic manner that may set up chain reactions of downstream events. If GABAergic activity is related to hyperexcitability in the IC, other synaptic transmitters may also be involved, such as glutamatergic synapses. Cochlear ablation can result in upregulation of the expression of the glutamate receptor and levels of glutamate, as well as larger and longer NMDA receptor-mediated currents in auditory brainstem and cortex neurons [27, 31, 32]. Given that most phenomena of hyperexcitability are found in animals deafened neonatally, considering the significance of age and development, adult ablation attempts have been made to assess variation due to age. Discrepancies do exist. No sign of significant sound-evoked excitation in the IC was found in adult animals after cochlear ablation [23, 33]. McAlpine [34] described contradictory results, showing a dramatic increase in the proportion of IC neurons excited by the intact ear in adult animals, although cochlear removal in infancy resulted in a larger increase in the responsiveness of individual neurons than did the same treatment in adult animals. Moreover, there is evidence that the AC exhibits higher responsiveness than the IC, and neonatal deafening at later ages produced greater effects on the AC than on the IC [35]. The question of whether there are age differences in neural responses to auditory deprivation needs to be explored further.

3. Partial Lesions of the Cochlea

The organ of Corti functions as a receptor to interpret sounds received and to transform them into electrical signals. Hair cells are the main elements in the organ of Corti that participate in this process. It is not difficult to understand that any external damage that leads to certain pathological alterations in the hair cells would impair signal transmission and therefore lead to a series of changes in the central auditory circuits. Even minor injuries to subcellular structures within the organ of Corti should be considered.

3.1. Outer Hair Cells (OHCs)

Cisplatin is known to have ototoxic side effects, acting especially on the organ of Corti. Hair cells are the primary target, especially OHCs. Tinnitus is a common consequence of cisplatin chemotherapy. Increased spontaneous activity in the dorsal cochlear nucleus (DCN) was shown to be a contributing factor in the etiology of tinnitus [6]. Cisplatin-treated hamsters display enhanced spontaneous activity within the DCN associated with the loss of OHCs, particularly in the high-frequency region [36–38]. Furthermore, hyperactivity in the DCN was correlated with the degree of OHC loss [36–38]. These results suggest that OHC loss may be a primary initiator in a series of events leading to tinnitus. Evidence based on clinical cases corroborates this hypothesis because patients suffering from tinnitus exhibit significantly lower amplitudes of otoacoustic emissions (generating from OHCs) than do persons without tinnitus [39]. Thus, it is assumed that reduced OHC activity is related to the generation of tinnitus.

3.2. Inner Hair Cells (IHCs)

Compared with cisplatin, carboplatin preferentially damages inner hair cells (IHCs) at relatively low doses [40] and has been characterized as a selective IHC loss toxin [32, 41–44]. Changes associated with IHC loss manifest as a significant reduction in the compound action potential (CAP) [41, 43], which reflects the summed neural output across the total population of auditory nerve fibers. Moreover, the amount of reduction is proportional to the extent of IHC loss [43]. However, a decline in output from inner hair cells does not result in a dramatic reduction in inferior colliculus potential (ICP) or auditory cortex potential (ACP) [43]. In some cases, ACP amplitudes remained unchanged and were even higher than those in the pre-carboplatin-treated group [43]. These results are also supported by examinations of neuronal properties in the IC, which showed no threshold or tuning curve shifts and no significant difference in potential amplitudes [43, 45, 46]. Both transient and sustained enhancement of AC potential have been observed, indicating that cortical circuits are involved in the process [43]. Taking the reduced cochlear output into account, even unchanged AC or IC neuronal activities are considered to provide increased gain in the auditory pathway. The degree of nonmonotonic rate-level functions (RLFs) is decreased in the IC following carboplatin treatment, indicating reduced inhibition in the IC [44].

3.3. Ribbon Synapses

Ribbon synapses are responsible for synchronous auditory signaling and transmitter release, and they have been implicated in temporal resolution [47–50]. It has been suggested that these synapses play an important role in sound coding. Recent findings show that ribbon synapses may be the primary target of low-dose gentamicin treatment without overt morphological disruptions [51]. IHC ribbon loss can also be a result of a mild level of noise exposure [52, 53]. Behaviorally tested tinnitus was associated with the loss of IHC ribbon synapses due to deafferentation [54, 55]. Additionally, Arc, an immediate early gene encoding activity-regulated cytoskeletal protein, which is involved in synapse scaling, was reduced in the AC as a result of ribbon loss [55]. Arc has been demonstrated to be upregulated in the brain under sensory-enriched conditions [56], suggesting reduced Arc levels as a correlate of deafferentation, consistent with results in the periphery. Moreover, in Arc knockout mice, sensory experiences can reduce the ability to scale down excitatory synapses [57]. The notion that IHC ribbon loss may cause synaptic scaling plasticity, particularly a more excited profile, in the central auditory pathway is worthy of examination in future studies.

4. Combined and Incomplete IHC and OHC Injuries (Acoustic Trauma)

Noise exposure is known to result in insults to hair cells (IHCs and OHCs, OHCs preferentially), impaired hearing sensitivity, and elevated hearing thresholds. Although it is likely that the characteristics of the noise, such as the frequency, intensity, and duration, determine the varying patterns of these effects, an overview is still of great value. Changes in the properties of neurons following noise-induced hearing impairment are often regarded as the mechanism underlying dysfunction of the integrated and sophisticated central auditory system. There has been much research regarding neuronal hyperactivity in recent decades. High-intensity acoustic overstimulation (e.g., 2.8 kHz, 105 dB SPL, and 2 h) substantially reduced the amplitude of CAP and increased the hearing threshold by about 15 dB at 1 kHz compared with a preexposure group [41], indicating that the gross output of the cochlea declines due to a loss of sensory cells. Moreover, the input of the cochlear nucleus (CN) (approximately the output of the cochlea) exhibits a similar pattern to CAP [41]. However, the local field potential of IC is reduced at low intensities but shows a rapid increase at higher intensities, finally exceeding the level before noise exposure [41]. In addition, the lowered CAP threshold and spontaneous firing rates in the IC seem to be correlated. A study by Mulders et al. showed that the spontaneous firing rate of IC neurons was in direct proportion to the degree of hearing loss; that is, the more severe the hearing loss was, the greater the increase in the spontaneous firing rate was [58]. Hyperactivity in the IC is also evidenced by increased spontaneous firing rates and high incidences of burst firing [59, 60]. This kind of hyperactivity has been found at different levels of the auditory pathway to varying degrees, such as in the ventral cochlear nucleus (VCN) [8, 61, 62], DCN [63–66], and AC [67–70]. For example, compared with the lower response amplitudes of the auditory brainstem after noise exposure, auditory middle latency response (MLR) amplitudes and the slopes of MLR amplitude intensity function were increased [71]. Because MLR is generated from a higher level of auditory pathways than ABR, it is considered that ABR suppression reflects noise-induced alterations at the periphery, whereas MLR enhancement indicates increased responding status in the central auditory system [71]. The underlying relationship between hyperactivity in the IC and DCN has drawn considerable interest. Resection of the DCN does not abolish behavioral signs of tinnitus [72]. A possible explanation is that a superior level of the central auditory pathway seems to take part in the pathological process. An immediate and significant elevation of spontaneous firing rates is observed in DCN and VCN after noise trauma, whereas IC activity remains unchanged. However, 2 weeks after exposure, increased IC activity begins to be detected, along with continuous hyperexcitation in the DCN [62]. Delayed IC hyperactivity may be a result of progressive influence of DCN hyperactivity on the higher level [72]. To further determine the relationship with cochlear activity, cochlear ablations have been manipulated at different periods after acoustic trauma. IC hyperactivity can be stopped by afferent drive blocking before 8 weeks after exposure, whereas, after this time period, cochlear ablation has no effect, and the neurons become endogenously excited independent of cochlear input [7, 8, 73]. These data suggest that there is progressive centralization of hyperactivity in the IC and a “window phase” (around 8 weeks) in the process [73]. Moreover, it is possible that the DCN serves to convey excitation to the IC [74]. Manzoor et al. [75] compared electrophysiological characteristics of noise-induced hyperactivity in the two nuclei and found that hyperactivity showed similar time courses and tonotopic patterns, although spontaneous activity was much lower in the IC than in the DCN.

One possible explanation for the enhanced activity in the auditory nuclei is that the profile of inhibition weakens after acoustic trauma [76]. For example, dendrites in the posterior ventral cochlear nucleus (PVCN) suffer a net loss of both excitatory and inhibitory endings at first; later, the net number of excitatory endings recovers greatly, whereas the inhibitory terminals recover only partially [77]. However, in the DCN, inhibitory neurons are far more dominant than excitatory neurons, compared with the VCN [78]. It is supposed that the loss of inhibitory synapses with acoustic trauma is greater in the DCN than in the VCN, and this may be a major reason that the DCN rather than the VCN initiates these excitatory events. The neurotransmitter system may be responsible for mediating this process. For example, a decrease in GABAergic inhibition in the DCN was found in mice with behavioral evidence of tinnitus [6]. Enhanced evoked responses in the DCN are found in noise-induced tinnitus mice as well. Moreover, blocking GABAergic synapses greatly enhanced the evoked response in control mice versus that in tinnitus mice, with blocking excitation slightly decreasing responses in tinnitus mice. This conclusion is supported by parallel experiments on the IC showing that a GABA antagonist does not cause significant changes in the temporal integration of noise-exposed animals [79]. Measurement of inhibitory receptor-related mRNA (GABA-A receptor subunit alpha 1, GABRA1, and glycine receptor subunit alpha 1) expression revealed a comparable trend, decreasing first and then increasing later [80], indicating that gene expression regulates the reduction in inhibition. Moreover, the localized region of reduced GABRA1 expression corresponds to the region where hyperactivity of IC neurons has been shown to develop [81]. An unmasking model has also been suggested as an explanation for hyperactivity after acoustic overstimulation [41, 76], consistent with cochlear ablation [24]. Moreover, Wang et al. further investigated the role of disinhibition after acoustic trauma and suggested that the inhibition may help sharpen the tuning curve and hold the excitatory responses within a narrow range [76]. Correlatively, disinhibition may expand the excitatory response and increase neuronal discharge rates, thus creating an overexcited profile.

5. Models for Reference

There are many models and results that can be used for comparison. Aminoglycoside antibiotics, known for causing “classical” ototoxicity, were used frequently in models of deafness in early research. Studies with this model found increased evoked c-Fos expression, indicating enhanced neuronal activity, and a marked decrease in GABA release from the central nucleus of the IC [82]. Due to extensive damage to the organ of Corti by aminoglycoside antibiotics, the interpretation of links between the lesion sites and these changes is limited.

Presbycusis, hearing loss as a consequence of aging, is characterized by a loss of hair cells, and downregulation of inhibition, both glycinergic and GABAergic, is found in the CN [83, 84], IC [85], and AC [85]. However, despite widespread reduction in inhibition, excitability of neurons in the IC shows little change [85]. Some neuroscientists favor the view that age-related changes in the IC have no obvious link to peripheral hearing loss. Those changes that are related to a decline in temporal processing seem to be due to aging in the auditory brainstem, somewhat independent of the peripheral deficits [86]. Because degenerative changes appear to occur in the brain with age, it is not easy to determine whether the peripheral deficits result in or are responses due to the central changes. Perhaps these are not mutually exclusive; both may occur to some extent. Clinicians have indicated that tinnitus often occurs together with presbycusis, especially in those with more severe degeneration of outer hair cells and stria vascularis [87]. Do hair cells have nothing to do with the brain? So far, the relationship between downregulation of inhibition and hearing loss and changes in the neuronal properties of the aged brain are unclear and require further examination.

Recently, an alternative model has been developed with salicylate administration and confirmed in humans [88]. Salicylate has been shown to increase both spontaneous and stimulus-driven activity widely across the circuits [89–94], extending such effects, to some extent, to acoustic trauma [92]. Moreover, downregulation of GABA-mediated inhibition has also been observed [93, 95]. OHCs appear to be the peripheral lesion site, inducing the subsequent consequences in the central system [88]. The relationship between the peripheral and central systems is still unclear. Moreover, instead of systemic application, local application of salicylate in the cochlea [93] and directly in the IC [89] and AC [94] suggests that induced hyperactivity originates in central pathways rather than in the cochlea. It is possible that some cochlear traumas, particularly those related to hair cell deficits, lead to increased excitation in the central auditory system as a result of unmasking of excitation or downregulation of inhibition, which may underpin tinnitus [96].

6. Homeostatic Plasticity and Other Potential Mechanisms

As the suggested mechanisms vary, no firm conclusion can yet be drawn. One of the most inclusive and plausible explanations is the theory of homeostatic plasticity, briefly, the ability of a neuronal network to maintain its present state [97]. When the central system detects reduced input from the cochlea, homeostatic compensation occurs, intensifying the intrinsic activity of neurons to maintain the mean firing rates unchanged in the circuits, as depicted in a computational model [5]. It can also be assumed that appropriate additional acoustic stimulation may reverse such hyperactivity [5]. This assumption is supported by the fact that tinnitus can be reversed by providing an enriched environment that matches the impaired frequencies [98, 99] or by repeatedly pairing tones with brief pulses of vagus nerve stimulation [100]. In addition, cross-model reorganization, realized years ago, seems to fit well with homeostatic compensation theory and may play a role in trauma-exposed auditory plasticity. For example, DCN responses have been found to be enhanced with trigeminal stimulation following a noise-induced reduction in auditory nerve inputs [101], as both auditory and somatosensory stimuli converge in the DCN. Although somatosensory input normally has a suppressive effect on DCN responding, long-term somatosensory stimuli in noise-exposed animals surprisingly reverse this suppression effect, especially in animals with tinnitus [102]. Furthermore, these cross-modal effects are considered to be widely distributed because a large proportion of neurons with somatosensory inputs are found to be vigorously active across the core auditory cortex without auditory stimulation [103].

An imbalance in synaptic strength represents another possible mechanism, as cochlear damage may be followed by downregulation of inhibition. Basically, this refers to the tendency of a neuronal network to stabilize the total synaptic strength [5, 97]. With downregulation of inhibition, excitation may scale up as a response. Inhibition seems, at least in part, more susceptible to plasticity than excitation is. In the domain of normal hearing, both inhibitory and excitatory transmission function; by contrast, in the domain of impaired hearing, inhibitory synaptic efficiency decreases [104]. Considering that a balance can be achieved by increasing inhibition or by decreasing excitation, both have been tested, with results indicating that enhanced inhibition, rather than reduced excitation, reverses tinnitus behavior [104]. Accordingly, if inhibitory strength is truly compromised, targeting inhibitory strength may offer potential for reversing or alleviating neuronal hyperactivity [105]. GABA receptor agonists were shown to reverse tone-exposure-induced hyperexcitability in the IC of rats [106] and to relieve tinnitus in humans [107]. It is clear that decreased inhibition is involved in tinnitus-related plasticity, but the extent of this involvement remains unclear. Thus, the question of whether reducing inhibition can induce or increase neural hyperactivity is worthy of further confirmation.

Recently, much importance has been attached to the role of ion channels in the pathology of the hyperactive auditory brain. Researchers have found that exposure to excessive noise causes reduced activity in the voltage-gated potassium channel Kv7, which induces DCN hyperactivity and leads to the development of tinnitus. Manipulations that increase Kv7 activity or reduce the activity of another type of voltage-gated potassium channel, the HCN channel, can help to prevent tinnitus-associated hyperactivity [108, 109]. The changes in ion channel activity may collaboratively contribute to the neuronal hyperactivity induced by noise exposure. To date, theories of homeostatic plasticity and the roles of these ion channels in the development of neural hyperactivity have been built on noise-exposed animal models, which need to be studied further in the other cochlear damage models.

7. Concluding Remarks

Based on the research reviewed, it seems likely that specific insults to the peripheral auditory system, including cochlear ablation, selective IHC or OHC loss, and noise-induced mixed and incomplete IHC and OHC injuries, result in a reduction of input from the cochlea, thereby giving rise to hyperactivity in the central auditory circuits. A good example of this process is found in tinnitus, which may be associated with neuronal hyperactivity and is likely a common consequence of various kinds of cochlear damage. From an evolutionary perspective, hyperactivity in the brain may be a maladaptive response to reduced input, indicating that the system needs to become more sensitive to the reduced input to obtain more information and thereby remain balanced and stable. This dysfunctional neural state might contribute to some brain pathologies with auditory dysfunction, as indicated in a recent review suggesting that hyperactivity in the auditory brain is closely related to tinnitus and hyperacusis [110]. Despite these findings, it is still too early to say that hyperactivity in the auditory brain follows cochlear damage. Hopefully, a better understanding of altered neural properties in response to cochlear damage will provide new insights into the mechanism of injury-induced central plasticity, suggesting novel strategies for therapies.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

This work is supported by the National Key Basic Research Program of China (no. 2014CB541705), the 12th Five-Year National Key Technologies R&D Program (no. 2012BAI12B01), and the National Natural Science Foundation of China (no. 81470688 and no. 81170920). The authors are grateful to Professor Shu Hui Wu for her careful review of this paper.

References

D. H. Sanes and S. M. N. Woolley, “A behavioral framework to guide research on central auditory development and plasticity,” Neuron, vol. 72, no. 6, pp. 912–929, 2011.

K. L. Johnson, T. Nicol, S. G. Zecker, and N. Kraus, “Developmental plasticity in the human auditory brainstem,” Journal of Neuroscience, vol. 28, no. 15, pp. 4000–4007, 2008.

T. N. Parks and E. W. Rubel, “Overview: development and plasticity of the central auditory system,” in Plasticity of the Auditory System, vol. 23 of Springer Handbook of Auditory Research, pp. 1–7, Springer, New York, NY, USA, 2004.

J. Syka, “Plastic changes in the central auditory system after hearing loss, restoration of function, and during learning,” Physiological Reviews, vol. 82, no. 3, pp. 601–636, 2002.

R. Schaette and R. Kempter, “Development of tinnitus-related neuronal hyperactivity through homeostatic plasticity after hearing loss: a computational model,” European Journal of Neuroscience, vol. 23, no. 11, pp. 3124–3138, 2006.

J. W. Middleton, T. Kiritani, C. Pedersen, J. G. Turner, G. M. G. Shepherd, and T. Tzounopoulos, “Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 18, pp. 7601–7606, 2011.

W. H. A. M. Mulders and D. Robertson, “Hyperactivity in the auditory midbrain after acoustic trauma: dependence on cochlear activity,” Neuroscience, vol. 164, no. 2, pp. 733–746, 2009.

D. Robertson, C. Bester, D. Vogler, and W. H. A. M. Mulders, “Spontaneous hyperactivity in the auditory midbrain: relationship to afferent input,” Hearing Research, vol. 295, pp. 124–129, 2013.

J. J. Eggermont and L. E. Roberts, “The neuroscience of tinnitus,” Trends in Neurosciences, vol. 27, no. 11, pp. 676–682, 2004.

M. Knipper, P. Van Dijk, I. Nunes, L. Rüttiger, and U. Zimmermann, “Advances in the neurobiology of hearing disorders: recent developments regarding the basis of tinnitus and hyperacusis,” Progress in Neurobiology, vol. 111, pp. 17–33, 2013.

P. Voss, “Sensitive and critical periods in visual sensory deprivation,” Frontiers in Psychology, vol. 4, article 664, 2013.

E. Kang, S. Durand, J. J. LeBlanc, T. K. Hensch, C. Chen, and M. Fagiolini, “Visual acuity development and plasticity in the absence of sensory experience,” The Journal of Neuroscience, vol. 33, no. 45, pp. 17789–17796, 2013.

C. Blakemore and G. F. Cooper, “Development of the brain depends on the visual environment,” Nature, vol. 228, no. 5270, pp. 477–478, 1970.

P. Gil-Loyzaga, M. C. Iglesias, F. Carricondo, M. V. Bartolomé, F. Rodríguez, and J. Poch-Broto, “Cochlear nuclei neuroplasticity after auditory nerve and cochlea removal,” Audiological Medicine, vol. 7, no. 1, pp. 29–39, 2009.

M. Zhang, X.-W. Chen, and Y.-S. Tian, “Neuronal degeneration of the auditory nervous center in the mouse model of cochlear ablation,” Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, vol. 44, no. 7, pp. 571–576, 2009.

S. R. Franklin, J. K. Brunso-Bechtold, and C. K. Henkel, “Unilateral cochlear ablation before hearing onset disrupts the maintenance of dorsal nucleus of the lateral lemniscus projection patterns in the rat inferior colliculus,” Neuroscience, vol. 143, no. 1, pp. 105–115, 2006.

S. R. Franklin, J. K. Brunso-Bechtold, and C. K. Henkel, “Bilateral cochlear ablation in postnatal rat disrupts development of banded pattern of projections from the dorsal nucleus of the lateral lemniscus to the inferior colliculus,” Neuroscience, vol. 154, no. 1, pp. 346–354, 2008.

H. Hildebrandt, N. A. Hoffmann, and R.-B. Illing, “Synaptic reorganization in the adult rat's ventral cochlear nucleus following its total sensory deafferentation,” PLoS ONE, vol. 6, no. 8, Article ID e23686, 2011.

J. C. Alvabado, V. Fuentes-Santamaria, S. R. Franklin, J. K. Brunso-Bechtold, and C. K. Henkel, “Synaptophysin and insulin-like growth factor-1 immunostaining in the central nucleus of the inferior colliculus in adult ferrets following unilateral cochlear removal: a densitometric analysis,” Synapse, vol. 61, no. 5, pp. 288–302, 2007.

S.-H. Oh, C.-S. Kim, and J.-J. Song, “Gene expression and plasticity in the rat auditory cortex after bilateral cochlear ablation,” Acta Oto-Laryngologica, vol. 127, no. 4, pp. 341–350, 2007.

S. K. Suneja, L. Yan, and S. J. Potashner, “Regulation of NT-3 and BDNF levels in guinea pig auditory brain stem nuclei after unilateral cochlear ablation,” Journal of Neuroscience Research, vol. 80, no. 3, pp. 381–390, 2005.

L. M. Kitzes and M. N. Semple, “Single-unit responses in the inferior colliculus: effects of neonatal unilateral cochlear ablation,” Journal of Neurophysiology, vol. 53, no. 6, pp. 1483–1500, 1985.

K. W. Nordeen, H. P. Killackey, and L. M. Kitzes, “Ascending projections to the inferior colliculus following unilateral cochlear ablation in the neonatal gerbil, Meriones unguiculatus,” Journal of Comparative Neurology, vol. 214, no. 2, pp. 144–153, 1983.

J. E. Mossop, M. J. Wilson, D. M. Caspary, and D. R. Moore, “Down-regulation of inhibition following unilateral deafening,” Hearing Research, vol. 147, no. 1-2, pp. 183–187, 2000.

L. M. Kitzes, “Some physiological consequences of neonatal cochlear destruction in the inferior colliculus of the gerbil, Meriones unguiculatus,” Brain Research, vol. 306, no. 1-2, pp. 171–178, 1984.

C. Vale and D. H. Sanes, “The effect of bilateral deafness on excitatory and inhibitory synaptic strength in the inferior colliculus,” European Journal of Neuroscience, vol. 16, no. 12, pp. 2394–2404, 2002.

V. C. Kotak, S. Fujisawa, F. A. Lee, O. Karthikeyan, C. Aoki, and D. H. Sanes, “Hearing loss raises excitability in the auditory cortex,” The Journal of Neuroscience, vol. 25, no. 15, pp. 3908–3918, 2005.

V. C. Kotak, A. E. Takesian, P. C. MacKenzie, and D. H. Sanes, “Rescue of inhibitory synapse strength following developmental hearing loss,” PLoS ONE, vol. 8, no. 1, Article ID e53438, 2013.

M. Argence, I. Saez, R. Sassu, I. Vassias, P. P. Vidal, and C. de Waele, “Modulation of inhibitory and excitatory synaptic transmission in rat inferior colliculus after unilateral cochleectomy: an in situ and immunofluorescence study,” Neuroscience, vol. 141, no. 3, pp. 1193–1207, 2006.

S. K. Suneja, S. J. Potashner, and C. G. Benson, “Plastic changes in glycine and GABA release and uptake in adult brain stem auditory nuclei after unilateral middle ear ossicle removal and cochlear ablation,” Experimental Neurology, vol. 151, no. 2, pp. 273–288, 1998.

A. G. Holt, M. Asako, C. A. Lomax et al., “Deafness-related plasticity in the inferior colliculus: gene expression profiling following removal of peripheral activity,” Journal of Neurochemistry, vol. 93, no. 5, pp. 1069–1086, 2005.

A. C. Lee and D. A. Godfrey, “Cochlear damage affects neurotransmitter chemistry in the central auditory system,” Frontiers in Neurology, vol. 5, article 227, 2014.

D. R. Moore and L. M. Kitzes, “Cochlear nucleus lesions in the adult gerbil: effects on neurone responses in the contralateral inferior colliculus,” Brain Research, vol. 373, no. 1-2, pp. 268–274, 1986.

D. McAlpine, R. L. Martin, J. E. Mossop, and D. R. Moore, “Response properties of neurons in the inferior colliculus of the monaurally deafened ferret to acoustic stimulation of the intact ear,” Journal of Neurophysiology, vol. 78, no. 2, pp. 767–779, 1997.

D. R. Moore and A. J. King, “Plasticity of binaural systems,” in Plasticity of the Auditory System, vol. 23 of Springer Handbook of Auditory Research, pp. 96–172, Springer, New York, NY, USA, 2004.

J. A. Kaltenbach, J. D. Rachel, T. A. Mathog, J. Zhang, P. R. Falzarano, and M. Lewandowski, “Cisplatin-induced hyperactivity in the dorsal cochlear nucleus and its relation to outer hair cell loss: relevance to tinnitus,” Journal of Neurophysiology, vol. 88, no. 2, pp. 699–714, 2002.

S. B. Melamed, J. A. Kaltenbach, M. W. Church, D. L. Burgio, and C. E. Afman, “Cisplatin-induced increases in spontaneous neural activity in the dorsal cochlear nucleus and associated outer hair cell loss,” Audiology, vol. 39, no. 1, pp. 24–29, 2000.

J. D. Rachel, J. A. Kaltenbach, and J. Janisse, “Increases in spontaneous neural activity in the hamster dorsal cochlear nucleus following cisplatin treatment: a possible basis for cisplatin-induced tinnitus,” Hearing Research, vol. 164, no. 1-2, pp. 206–214, 2002.

D. Modh, A. Katarkar, N. Alam, A. Jain, and P. Shah, “Relation of distortion product otoacoustic emission and tinnitus in normal hearing patients: a pilot study,” Noise and Health, vol. 16, no. 69, pp. 69–72, 2014.

P. Hofstetter, D. Ding, N. Powers, and R. J. Salvi, “Quantitative relationship of carboplatin dose to magnitude of inner and outer hair cell loss and the reduction in distortion product otoacoustic emission amplitude in chinchillas,” Hearing Research, vol. 112, no. 1-2, pp. 199–215, 1997.

R. J. Salvi, J. Wang, and D. Ding, “Auditory plasticity and hyperactivity following cochlear damage,” Hearing Research, vol. 147, no. 1-2, pp. 261–274, 2000.

C. A. Bauer, J. G. Turner, D. M. Caspary, K. S. Myers, and T. J. Brozoski, “Tinnitus and inferior colliculus activity in chinchillas related to three distinct patterns of cochlear trauma,” Journal of Neuroscience Research, vol. 86, no. 11, pp. 2564–2578, 2008.

C. Qiu, R. Salvi, D. Ding, and R. Burkard, “Inner hair cell loss leads to enhanced response amplitudes in auditory cortex of unanesthetized chinchillas: evidence for increased system gain,” Hearing Research, vol. 139, no. 1-2, pp. 153–171, 2000.

A. Alkhatib, U. W. Biebel, and J. W. T. Smolders, “Reduction of inhibition in the inferior colliculus after inner hair cell loss,” NeuroReport, vol. 17, no. 14, pp. 1493–1497, 2006.

S. L. McFadden, C. Kasper, J. Ostrowski, D. Ding, and R. J. Salvi, “Effects of inner hair cell loss on inferior colliculus evoked potential thresholds, amplitudes and forward masking functions in chinchillas,” Hearing Research, vol. 120, no. 1-2, pp. 121–132, 1998.

M. Wake, S. Takeno, R. J. Mount, and R. V. Harrison, “Recording from the inferior colliculus following cochlear inner hair cell damage,” Acta Oto-Laryngologica, vol. 116, no. 5, pp. 714–720, 1996.

E. Glowatzki and P. A. Fuchs, “Transmitter release at the hair cell ribbon synapse,” Nature Neuroscience, vol. 5, no. 2, pp. 147–154, 2002.

S. Safieddine, A. El-Amraoui, and C. Petit, “The auditory hair cell ribbon synapse: from assembly to function,” Annual Review of Neuroscience, vol. 35, pp. 509–528, 2012.

D. Khimich, R. Nouvtan, R. Pujol et al., “Hair cell synaptic ribbons are essential for synchronous auditory signalling,” Nature, vol. 434, no. 7035, pp. 889–894, 2005.

B. N. Buran, N. Strenzke, A. Neef, E. D. Gundelfinger, T. Moser, and M. C. Liberman, “Onset coding is degraded in auditory nerve fibers from mutant mice lacking synaptic ribbons,” Journal of Neuroscience, vol. 30, no. 22, pp. 7587–7597, 2010.

K. Liu, X. Jiang, C. Shi et al., “Cochlear inner hair cell ribbon synapse is the primary target of ototoxic aminoglycoside stimuli,” Molecular Neurobiology, vol. 48, no. 3, pp. 647–654, 2013.

L. Shi, L. Liu, T. He et al., “Ribbon synapse plasticity in the cochleae of guinea pigs after noise-induced silent damage,” PLoS ONE, vol. 8, no. 12, Article ID e81566, 2013.

S. F. Maison, H. Usubuchi, and M. C. Liberman, “Efferent feedback minimizes cochlear neuropathy from moderate noise exposure,” Journal of Neuroscience, vol. 33, no. 13, pp. 5542–5552, 2013.

L. Rüttiger, W. Singer, R. Panford-Walsh et al., “The reduced cochlear output and the failure to adapt the central auditory response causes tinnitus in noise exposed rats,” PLoS ONE, vol. 8, no. 3, Article ID e57247, 2013.

W. Singer, A. Zuccotti, M. Jaumann et al., “Noise-induced inner hair cell ribbon loss disturbs central arc mobilization: a novel molecular paradigm for understanding tinnitus,” Molecular Neurobiology, vol. 47, no. 1, pp. 261–279, 2013.

R. Pinaud, M. R. Penner, H. A. Robertson, and R. W. Currie, “Upregulation of the immediate early gene arc in the brains of rats exposed to environmental enrichment: implications for molecular plasticity,” Molecular Brain Research, vol. 91, no. 1-2, pp. 50–56, 2001.

M. Gao, K. Sossa, L. Song et al., “A specific requirement of Arc/Arg3.1 for visual experience-induced homeostatic synaptic plasticity in mouse primary visual cortex,” The Journal of Neuroscience, vol. 30, no. 21, pp. 7168–7178, 2010.

W. H. A. M. Mulders, D. Ding, R. Salvi, and D. Robertson, “Relationship between auditory thresholds, central spontaneous activity, and hair cell loss after acoustic trauma,” Journal of Comparative Neurology, vol. 519, no. 13, pp. 2637–2647, 2011.

B. Coomber, J. I. Berger, V. L. Kowalkowski, T. M. Shackleton, A. R. Palmer, and M. N. Wallace, “Neural changes accompanying tinnitus following unilateral acoustic trauma in the guinea pig,” European Journal of Neuroscience, vol. 40, no. 2, pp. 2427–2441, 2014.

F. Wang, L. Zuo, B. Hong et al., “Tonotopic reorganization and spontaneous firing in inferior colliculus during both short and long recovery periods after noise overexposure,” Journal of Biomedical Science, vol. 20, article 91, 2013.

D. P. Vogler, D. Robertson, and W. H. A. M. Mulders, “Hyperactivity in the ventral cochlear nucleus after cochlear trauma,” Journal of Neuroscience, vol. 31, no. 18, pp. 6639–6645, 2011.

M. Gröschel, J. Ryll, R. Götze, A. Ernst, and D. Basta, “Acute and long-term effects of noise exposure on the neuronal spontaneous activity in cochlear nucleus and inferior colliculus brain slices,” BioMed Research International, vol. 2014, Article ID 909260, 8 pages, 2014.

T. J. Brozoski, C. A. Bauer, and D. M. Caspary, “Elevated fusiform cell activity in the dorsal cochlear nucleus of chinchillas with psychophysical evidence of tinnitus,” The Journal of Neuroscience, vol. 22, no. 6, pp. 2383–2390, 2002.

P. G. Finlayson and J. A. Kaltenbach, “Alterations in the spontaneous discharge patterns of single units in the dorsal cochlear nucleus following intense sound exposure,” Hearing Research, vol. 256, no. 1-2, pp. 104–117, 2009.

J. A. Kaltenbach and C. E. Afman, “Hyperactivity in the dorsal cochlear nucleus after intense sound exposure and its resemblance to tone-evoked activity: a physiological model for tinnitus,” Hearing Research, vol. 140, no. 1-2, pp. 165–172, 2000.

N. Pilati, C. Large, I. D. Forsythe, and M. Hamann, “Acoustic over-exposure triggers burst firing in dorsal cochlear nucleus fusiform cells,” Hearing Research, vol. 283, no. 1-2, pp. 98–106, 2012.

J. Syka and N. Rybalko, “Threshold shifts and enhancement of cortical evoked responses after noise exposure in rats,” Hearing Research, vol. 139, no. 1-2, pp. 59–68, 2000.

W. Sun, L. Zhang, J. Lu, G. Yang, E. Laundrie, and R. Salvi, “Noise exposure-induced enhancement of auditory cortex response and changes in gene expression,” Neuroscience, vol. 156, no. 2, pp. 374–380, 2008.

W. Sun, A. Deng, A. Jayaram, and B. Gibson, “Noise exposure enhances auditory cortex responses related to hyperacusis behavior,” Brain Research, vol. 1485, pp. 108–116, 2012.

J. Wang, D. Caspary, and R. J. Salvi, “GABA-A antagonist causes dramatic expansion of tuning in primary auditory cortex,” NeuroReport, vol. 11, no. 5, pp. 1137–1140, 2000.

J. Popelar, J. Grecova, N. Rybalko, and J. Syka, “Comparison of noise-induced changes of auditory brainstem and middle latency response amplitudes in rats,” Hearing Research, vol. 245, no. 1-2, pp. 82–91, 2008.

T. J. Brozoski and C. A. Bauer, “The effect of dorsal cochlear nucleus ablation on tinnitus in rats,” Hearing Research, vol. 206, no. 1-2, pp. 227–236, 2005.

W. H. A. M. Mulders and D. Robertson, “Progressive centralization of midbrain hyperactivity after acoustic trauma,” Neuroscience, vol. 192, pp. 753–760, 2011.

N. F. Manzoor, F. G. Licari, M. Klapchar et al., “Noise-induced hyperactivity in the inferior colliculus: its relationship with hyperactivity in the dorsal cochlear nucleus,” Journal of Neurophysiology, vol. 108, no. 4, pp. 976–988, 2012.

N. F. Manzoor, Y. Gao, F. Licari, and J. A. Kaltenbach, “Comparison and contrast of noise-induced hyperactivity in the dorsal cochlear nucleus and inferior colliculus,” Hearing Research, vol. 295, pp. 114–123, 2013.

J. Wang, D. Ding, and R. J. Salvi, “Functional reorganization in chinchilla inferior colliculus associated with chronic and acute cochlear damage,” Hearing Research, vol. 168, no. 1-2, pp. 238–249, 2002.

J. J. Kim, J. Gross, D. K. Morest, and S. J. Potashner, “Quantitative study of degeneration and new growth of axons and synaptic endings in the chinchilla cochlear nucleus after acoustic overstimulation,” Journal of Neuroscience Research, vol. 77, no. 6, pp. 829–842, 2004.

M. Fredrich, A. Reisch, and R.-B. Illing, “Neuronal subtype identity in the rat auditory brainstem as defined by molecular profile and axonal projection,” Experimental Brain Research, vol. 195, no. 2, pp. 241–260, 2009.

W. S. Szczepaniak and A. R. Møller, “Evidence of decreased GA$Aergic influence on temporal integration in the inferior colliculus following acute noise exposure: a study of evoked potentials in the rat,” Neuroscience Letters, vol. 196, no. 1-2, pp. 77–80, 1995.

S. Dong, W. H. A. M. Mulders, J. Rodger, S. Woo, and D. Robertson, “Acoustic trauma evokes hyperactivity and changes in gene expression in guinea-pig auditory brainstem,” European Journal of Neuroscience, vol. 31, no. 9, pp. 1616–1628, 2010.

S. Dong, J. Rodger, W. H. A. M. Mulders, and D. Robertson, “Tonotopic changes in GABA receptor expression in guinea pig inferior colliculus after partial unilateral hearing loss,” Brain Research, vol. 1342, pp. 24–32, 2010.

S. C. Bledsoe Jr., S. Nagase, J. M. Miller, and R. A. Altschuler, “Deafness-induced plasticity in the mature central auditory system,” NeuroReport, vol. 7, no. 1, pp. 225–229, 1995.

H. Wang, J. G. Turner, L. Ling, J. L. Parrish, L. F. Hughes, and D. M. Caspary, “Age-related changes in glycine receptor subunit composition and binding in dorsal cochlear nucleus,” Neuroscience, vol. 160, no. 1, pp. 227–239, 2009.

R. Xie and P. B. Manis, “Glycinergic synaptic transmission in the cochlear nucleus of mice with normal hearing and age-related hearing loss,” Journal of Neurophysiology, vol. 110, no. 8, pp. 1848–1859, 2013.

J. Syka, “The Fischer 344 rat as a model of presbycusis,” Hearing Research, vol. 264, no. 1-2, pp. 70–78, 2010.

R. D. Frisina and J. P. Walton, “Age-related structural and functional changes in the cochlear nucleus,” Hearing Research, vol. 216-217, no. 1-2, pp. 216–223, 2006.

K. Terao, S. Cureoglu, P. A. Schachern et al., “Cochlear changes in presbycusis with tinnitus,” American Journal of Otolaryngology—Head and Neck Medicine and Surgery, vol. 32, no. 3, pp. 215–220, 2011.

Y. Cazals, “Auditory sensori-neural alterations induced by salicylate,” Progress in Neurobiology, vol. 62, no. 6, pp. 583–631, 2000.

D. Basta, R. Goetze, and A. Ernst, “Effects of salicylate application on the spontaneous activity in brain slices of the mouse cochlear nucleus, medial geniculate body and primary auditory cortex,” Hearing Research, vol. 240, no. 1-2, pp. 42–51, 2008.

L. Wei, D. Ding, W. Sun, M. A. Xu-Friedman, and R. Salvi, “Effects of sodium salicylate on spontaneous and evoked spike rate in the dorsal cochlear nucleus,” Hearing Research, vol. 267, no. 1-2, pp. 54–60, 2010.

D. Stolzberg, M. Chrostowski, R. J. Salvi, and B. L. Allman, “Intracortical circuits amplify sound-evoked activity in primary auditory cortex following systemic injection of salicylate in the rat,” Journal of Neurophysiology, vol. 108, no. 1, pp. 200–214, 2012.

A. J. Noreña, G. Moffat, J. L. Blanc, L. Pezard, and Y. Cazals, “Neural changes in the auditory cortex of awake guinea pigs after two tinnitus inducers: salicylate and acoustic trauma,” Neuroscience, vol. 166, no. 4, pp. 1194–1209, 2010.

W. Sun, J. Lu, D. Stolzberg et al., “Salicylate increases the gain of the central auditory system,” Neuroscience, vol. 159, no. 1, pp. 325–334, 2009.

G.-D. Chen, D. Stolzberg, E. Lobarinas, W. Sun, D. Ding, and R. Salvi, “Salicylate-induced cochlear impairments, cortical hyperactivity and re-tuning, and tinnitus,” Hearing Research, vol. 295, pp. 100–113, 2013.

J. Lu, E. Lobarinas, A. Deng et al., “GABAergic neural activity involved in salicylate-induced auditory cortex gain enhancement,” Neuroscience, vol. 189, pp. 187–198, 2011.

S. Hébert, P. Fournier, and A. Noreña, “Auditory sensitivity is increased in tinnitus ears,” Journal of Neuroscience, vol. 33, no. 6, pp. 2356–2364, 2013.

G. G. Turrigiano, “Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same,” Trends in Neurosciences, vol. 22, no. 5, pp. 221–227, 1999.

A. J. Noreña and J. J. Eggermont, “Enriched acoustic environment after noise trauma abolishes neural signs of tinnitus,” NeuroReport, vol. 17, no. 6, pp. 559–563, 2006.

A. J. Noreña and J. J. Eggermont, “Enriched acoustic environment after noise trauma reduces hearing loss and prevents cortical map reorganization,” Journal of Neuroscience, vol. 25, no. 3, pp. 699–705, 2005.

N. D. Engineer, J. R. Riley, J. D. Seale et al., “Reversing pathological neural activity using targeted plasticity,” Nature, vol. 470, no. 7332, pp. 101–104, 2011.

S. E. Shore, S. Koehler, M. Oldakowski, L. F. Hughes, and S. Syed, “Dorsal cochlear nucleus responses to somatosensory stimulation are enhanced after noise-induced hearing loss,” European Journal of Neuroscience, vol. 27, no. 1, pp. 155–168, 2008.

S. Dehmel, S. Pradhan, S. Koehler, S. Bledsoe, and S. Shore, “Noise overexposure alters long-term somatosensory-auditory processing in the dorsal cochlear nucleus—possible basis for tinnitus-related hyperactivity?” Journal of Neuroscience, vol. 32, no. 5, pp. 1660–1671, 2012.

M. A. Meredith, L. P. Keniston, and B. L. Allman, “Multisensory dysfunction accompanies crossmodal plasticity following adult hearing impairment,” Neuroscience, vol. 214, pp. 136–148, 2012.

S. Yang, B. D. Weiner, L. S. Zhang, S.-J. Cho, and S. Bao, “Homeostatic plasticity drives tinnitus perception in an animal model,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 36, pp. 14974–14979, 2011.

B. D. Richardson, T. J. Brozoski, L. L. Ling, and D. M. Caspary, “Targeting inhibitory neurotransmission in tinnitus,” Brain Research, vol. 1485, pp. 77–87, 2012.

W. S. Szczepaniak and A. R. Møller, “Effects of (-)-baclofen, clonazepam, and diazepam on tone exposure-induced hyperexcitability of the inferior colliculus in the rat: possible therapeutic implications for pharmacological management of tinnitus and hyperacusis,” Hearing Research, vol. 97, no. 1-2, pp. 46–53, 1996.

R. M. Johnson, R. Brummett, and A. Schleuning, “Use of alprazolam for relief of tinnitus: a double-blind study,” Archives of Otolaryngology—Head and Neck Surgery, vol. 119, no. 8, pp. 842–845, 1993.

S. Li, B. I. Kalappa, and T. Tzounopoulos, “Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus,” eLife, vol. 4, Article ID e07242, 2015.

S. Li, V. Choi, and T. Tzounopoulos, “Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 24, pp. 9980–9985, 2013.

B. D. Auerbach, P. V. Rodrigues, and R. J. Salvi, “Central gain control in tinnitus and hyperacusis,” Frontiers in Neurology, vol. 5, article 206, 2014.