Tinnitus Generation Research Articles

Alterations to the attention system in adults with tinnitus are modality specific

Generation and persistence of tinnitus following hearing loss may be due to aberrant engagement of attention. Here, functional MRI was used to determine differences in auditory and visual attention processing in adults with tinnitus and hearing loss compared to two age-matched control groups, one with matched hearing loss and the other with normal hearing thresholds. Attentional processing was investigated using a short-term memory task with varying loads, employing unfamiliar Korean letters in the visual condition and non-speech sounds in the auditory condition. We found similar behavioral response across the three groups for both modalities and tasks. For the auditory modality, the response of the attention network was suppressed in the tinnitus group compared to the control groups for both task loads, with the effect being more pronounced at high load. In contrast, in the visual modality, the tinnitus group exhibited greater response of the attention network, regardless of memory load, compared to the control groups. The results increase our understanding of the neural mechanisms of tinnitus and suggest that interventions that manipulate attention, especially in the visual domain, should be further investigated.

Dysfunctional Noise Cancelling of the Rostral Anterior Cingulate Cortex in Tinnitus Patients

BackgroundPeripheral auditory deafferentation and central compensation have been regarded as the main culprits of tinnitus generation. However, patient-to-patient discrepancy in the range of the percentage of daytime in which tinnitus is perceived (tinnitus awareness percentage, 0 – 100%), is not fully explicable only by peripheral deafferentation, considering that the deafferentation is a stable persisting phenomenon but tinnitus is intermittently perceived in most patients. Consequently, the involvement of a dysfunctional noise cancellation mechanism has recently been suggested with regard to the individual differences in reported tinnitus awareness. By correlating the tinnitus awareness percentage with resting-state source-localized electroencephalography findings, we may be able to retrieve the cortical area that is negatively correlated with tinnitus awareness percentage, and then the area may be regarded as the core of the noise cancelling system that is defective in patients with tinnitus.Methods and FindingsUsing resting-state cortical oscillation, we investigated 80 tinnitus patients by correlating the tinnitus awareness percentage with their source-localized cortical oscillatory activity and functional connectivity. The activity of bilateral rostral anterior cingulate cortices (ACCs), left dorsal- and pregenual ACCs for the delta band, bilateral rostral/pregenual/subgenual ACCs for the theta band, and left rostral/pregenual ACC for the beta 1 band displayed significantly negative correlations with tinnitus awareness percentage. Also, the connectivity between the left primary auditory cortex (A1) and the rostral ACC, as well as between the left A1 and the subgenual ACC for the beta 1 band, were negatively correlated with tinnitus awareness percentage.ConclusionsThese results may designate the role of the rostral ACC as the core of the descending noise cancellation system, and thus dysfunction of the rostral ACC may result in perception of tinnitus. The present study also opens a possibility of tinnitus modulation by neuromodulatory approaches targeting the rostral ACC.

Relationship between intracochlear electrode position and tinnitus in cochlear implantees

Conclusion: Cochlear implant electrode position has an impact on the rate of tinnitus suppression and generation. Objective: Suppression of pre-operative tinnitus or a generation of a new tinnitus in cochlear implantees is a known effect of cochlear implantation. The aim of the current study was to evaluate different cochlear implant electrode positions and their relationship with tinnitus suppression and tinnitus generation. Method: This study retrospectively evaluated four groups of CI recipients with radiologically evaluated electrode positions in relation to their subjective tinnitus quality, as evaluated by an analogue loudness scale (ALS) and a questionnaire. Group 1 consisted of 19 patients with a scalar change of the electrode position. Group 2 consisted of 18 patients with a scala tympani position and a perimodiolar electrode. Group 3 consisted of 10 patients with a scala tympani position and a lateral wall electrode. Group 4 consisted of eight patients with a scala vestibuli position. Results: An overall tinnitus suppression rate of 45.9% and a generation of a new tinnitus or the deterioration of an existing one of 5.6% were observed. A significant difference in tinnitus suppression was found between groups 1 and groups 2, 3, and 4 in tinnitus suppression and tinnitus generation.

Modulating central gain in tinnitus: changes in nitric oxide synthase in the ventral cochlear nucleus.

A significant challenge in tinnitus research lies in explaining how acoustic insult leads to tinnitus in some individuals, but not others. One possibility is genetic variability in the expression and function of neuromodulators – components of neural signaling that alter the balance of excitation and inhibition in neural circuits. An example is nitric oxide (NO) – a free radical and potent neuromodulator in the mammalian brain – that regulates plasticity via both pre-synaptic and postsynaptic mechanisms. Changes in NO have previously been implicated in tinnitus generation, specifically in the ventral cochlear nucleus (VCN). Here, we examined nitric oxide synthase (NOS) – the enzyme responsible for NO production – in the guinea pig VCN following acoustic trauma. NOS was present in most cell types – including spherical and globular bushy cells, small, medium, and large multipolar cells, and octopus cells – spanning the entire extent of the VCN. The staining pattern was symmetrical in control animals. Unilateral acoustic over-exposure (AOE) resulted in marked asymmetries between ipsilateral and contralateral sides of the VCN in terms of the distribution of NOS across the cochlear nuclei in animals with behavioral evidence of tinnitus: fewer NOS-positive cells and a reduced level of NOS staining was present across the whole extent of the contralateral VCN, relative to the ipsilateral VCN. The asymmetric pattern of NOS-containing cells was observed as early as 1 day after AOE and was also present in some animals at 3, 7, and 21 days after AOE. However, it was not until 8 weeks after AOE, when tinnitus had developed, that asymmetries were significant overall, compared with control animals. Asymmetrical NOS expression was not correlated with shifts in the threshold hearing levels. Variability in NOS expression between animals may represent one underlying difference that can be linked to whether or not tinnitus develops after noise exposure.

The Potential Role of the Medial Olivocochlear Bundle in the Generation of Tinnitus

The physiology of the efferent cochlear innervation and the pathophysiology of tinnitus are 2 important but rather obscure chapters of neuro-otology. The possible interference of the medial olivocochlear bundle (MOCB) in the pathophysiology of tinnitus is not only a matter of strong controversy but also a field with possible important clinical and therapeutic implications. The aim of this study was to reveal the differences in study population, design, and methodology that may have attributed the conflicting results in the existing clinical trials. A review of the relevant literature published between January 1990 and June 2013 was conducted via the PubMed database (www.pubmed.org) with the search terms "tinnitus" and "otoacoustic emissions and suppression or efferent." Clinical studies on patients with additional pathologic abnormalities that may implicate the MOCB, such as hyperacousis or auditory neuropathy, were excluded. The 15 relevant studies were reviewed for critical differences in the recruitment of their study population and control group, as well as their methods of testing and evaluating the results. The different methods and study parameters are compared to each other. Factors known to attribute different MOCB responses, possibly responsible for the controversial results, are highlighted. The remarkable heterogeneity of the existing studies does not allow for safe conclusions. Insufficient knowledge on the physiology of the MOCB reflex seems to preclude the formation of a consensus on the optimal protocol for the evaluation of its function. Further research is definitely needed.

WPŁYW SZUMÓW USZNYCH I NIEDOSŁUCHU ZWIĄZANEGO Z WIEKIEM NA SUPRESJĘ KONTRALATERALNĄ EMISJI OTOAKUSTYCZNEJ

BackgroundThe medial olivocochlear system (MOCS), part of the efferent auditory pathway, causes an inhibitory effect on the outer hair cells, thus protecting them against extreme noise exposure and improving speech discrimination in noisy environments. This study aims to assess the MOCS function and aging in tinnitus patients with the use of contralateral suppression (CS) of otoacoustic emissions (OAEs).Material and Methods136 subjects took part in this study, divided in 6 groups (control group, right-side tinnitus, left-side tinnitus, bilateral tinnitus, presbycusis without tinnitus and presbycusis with tinnitus). CS of transiently- evoked (TEOAEs) and distortion products OAEs (DPOAEs) was measured for each group and pair- wise comparisons between the groups were performed.ResultsCS was less frequent and the mean values of CS were significantly lower in the tinnitus ears than normal ones. The mean values of CS of ears with presbycusis were in some cases higher than ears with presbycusis and tinnitus and also than ears with tinnitus and normal hearing. Not particular statistical differences were found between the method used (TEOAEs or DPOAEs) and the comparisons between the groups.ConclusionsThe absence and lower values of CS in tinnitus ears imply a MOCS dysfunction as a main factor of tinnitus generation. Tinnitus seems to have a more detrimental effect to the MOCS function than presbycusis. CS of TEOAEs and DPOAEs are equally sensitive methods in detecting MOCS dysfunction in patients with tinnitus.

Both central and peripheral auditory systems are involved in salicylate-induced tinnitus in rats: a behavioral study.

ObjectiveThis study was designed to establish a low dose salicylate-induced tinnitus rat model and to investigate whether central or peripheral auditory system is involved in tinnitus.MethodsLick suppression ratio (R), lick count and lick latency of conditioned rats in salicylate group (120 mg/kg, intraperitoneally) and saline group were first compared. Bilateral auditory nerves were ablated in unconditioned rats and lick count and lick latency were compared before and after ablation. The ablation was then performed in conditioned rats and lick count and lick latency were compared between salicylate group and saline group and between ablated and unablated salicylate groups.ResultsBoth the R value and the lick count in salicylate group were significantly higher than those in saline group and lick latency in salicylate group was significantly shorter than that in saline group. No significant changes were observed in lick count and lick latency before and after ablation. After ablation, lick count and lick latency in salicylate group were significantly higher and shorter respectively than those in saline group, but they were significantly lower and longer respectively than those in unablated salicylate group.ConclusionA low dose of salicylate (120 mg/kg) can induce tinnitus in rats and both central and peripheral auditory systems participate in the generation of salicylate-induced tinnitus.

Effects of furosemide on cochlear neural activity, central hyperactivity and behavioural tinnitus after cochlear trauma in guinea pig.

Cochlear trauma causes increased spontaneous activity (hyperactivity) to develop in central auditory structures, and this has been suggested as a neural substrate for tinnitus. Using a guinea pig model we have previously demonstrated that for some time after cochlear trauma, central hyperactivity is dependent on peripheral afferent drive and only later becomes generated intrinsically within central structures. Furosemide, a loop diuretic, reduces spontaneous firing of auditory afferents. We investigated in our guinea pig model the efficacy of furosemide in reducing 1) spontaneous firing of auditory afferents, using the spectrum of neural noise (SNN) from round window recording, 2) hyperactivity in inferior colliculus, using extracellular single neuron recordings and 3) tinnitus at early time-points after cochlear trauma. Tinnitus was assessed using gap prepulse inhibition of acoustic startle (GPIAS). Intraperitoneal furosemide, but not saline, caused a marked decrease in both SNN and central hyperactivity. Intracochlear perfusion with furosemide similarly reversed central hyperactivity. In animals in which GPIAS measurements suggested the presence of tinnitus (reduced GPIAS), this could be reversed with an intraperitoneal injection with furosemide but not saline. The results are consistent with furosemide reducing central hyperactivity and behavioural signs of tinnitus by acting peripherally to decrease spontaneous firing of auditory afferents. The data support the notion that hyperactivity may be involved in the generation of tinnitus and further suggest that there may be a therapeutic window after cochlear trauma using drug treatments that target peripheral spontaneous activity.

Modulation of gene expression in guinea pig paraflocculus after induction of hearing loss.

Hearing loss often results in plastic changes in the central auditory pathways, which may be involved in the generation of tinnitus, a phantom auditory sensation. However, although animal studies have consistently shown increased neural activity in auditory structures after hearing loss, tinnitus does not always develop. It has therefore been suggested that non-auditory structures perform a gating or regulatory role that determines whether the increased activity in auditory structures leads to conscious perception. Recent evidence points to the paraflocculus of the cerebellum as having such a role. Therefore, we investigated the early effects of hearing loss on gene expression in guinea pig paraflocculus. Gene expression was investigated after two weeks recovery from either acoustic or mechanical cochlear trauma. The genes investigated in our study were associated with inhibitory neurotransmission (GABA-A receptor subunit alpha 1; glutamate decarboxylase 1), excitatory neurotransmission (glutamate receptor NMDA subunit 1), and regulation of transmitter release (member of RAB family of small GTPase). Our results show increased mRNA levels of glutamate decarboxylase 1 in ipsilateral paraflocculus with no difference between the different methods of cochlear trauma. Early modulation of gene expression in the paraflocculus suggests that an early effect of hearing loss may affect the influence of this structure on auditory processing.

Modulation of gene expression in guinea pig paraflocculus after induction of hearing loss

Hearing loss often results in plastic changes in the central auditory pathways, which may be involved in the generation of tinnitus, a phantom auditory sensation. However, although animal studies have consistently shown increased neural activity in auditory structures after hearing loss, tinnitus does not always develop. It has therefore been suggested that non-auditory structures perform a gating or regulatory role that determines whether the increased activity in auditory structures leads to conscious perception. Recent evidence points to the paraflocculus of the cerebellum as having such a role. Therefore, we investigated the early effects of hearing loss on gene expression in guinea pig paraflocculus. Gene expression was investigated after two weeks recovery from either acoustic or mechanical cochlear trauma. The genes investigated in our study were associated with inhibitory neurotransmission (GABA-A receptor subunit alpha 1; glutamate decarboxylase 1), excitatory neurotransmission (glutamate receptor NMDA subunit 1), and regulation of transmitter release (member of RAB family of small GTPase). Our results show increased mRNA levels of glutamate decarboxylase 1 in ipsilateral paraflocculus with no difference between the different methods of cochlear trauma. Early modulation of gene expression in the paraflocculus suggests that an early effect of hearing loss may affect the influence of this structure on auditory processing.

Modulation of gene expression in guinea pig paraflocculus after induction of hearing loss

Hearing loss often results in plastic changes in the central auditory pathways, which may be involved in the generation of tinnitus, a phantom auditory sensation. However, although animal studies have consistently shown increased neural activity in auditory structures after hearing loss, tinnitus does not always develop. It has therefore been suggested that non-auditory structures perform a gating or regulatory role that determines whether the increased activity in auditory structures leads to conscious perception. Recent evidence points to the paraflocculus of the cerebellum as having such a role. Therefore, we investigated the early effects of hearing loss on gene expression in guinea pig paraflocculus. Gene expression was investigated after two weeks recovery from either acoustic or mechanical cochlear trauma. The genes investigated in our study were associated with inhibitory neurotransmission (GABA-A receptor subunit alpha 1; glutamate decarboxylase 1), excitatory neurotransmission (glutamate receptor NMDA subunit 1), and regulation of transmitter release (member of RAB family of small GTPase). Our results show increased mRNA levels of glutamate decarboxylase 1 in ipsilateral paraflocculus with no difference between the different methods of cochlear trauma. Early modulation of gene expression in the paraflocculus suggests that an early effect of hearing loss may affect the influence of this structure on auditory processing.

Targeting the parahippocampal area by auditory cortex stimulation in tinnitus.

The final common pathway in tinnitus generation is considered to be synchronized auditory oscillatory hyperactivity. Intracranial auditory cortex stimulation (iACS) via implanted electrodes has been developed to treat severe cases of intractable tinnitus targeting this final common pathway, in the hope of being a panacea for tinnitus. However, not everybody responds to this treatment. The electrical brain activity and functional connectivity at rest might determine who is going to respond or not to iACS and might shed light on the pathophysiology of auditory phantom sound generation. The resting state electrical brain activity of 5 patients who responded and 5 patients who did not respond to auditory cortex implantation are compared using source localized spectral activity (Z-score of log transformed current density) and lagged phase synchronization. sLORETA source localization reveals significant differences between responders vs non-responders for beta3 in left posterior parahippocampal, hippocampal and amygdala area extending into left insula. Gamma band differences exist in the posterior parahippocampal areas and BA10. Functional connectivity between the auditory cortex and the hippocampal area is increased for beta2, delta and theta2 in responders, as well as between the parahippocampal area and auditory cortex for beta3. The resting state functional connectivity and activity between the auditory cortex and parahippocampus might determine whether a tinnitus patient will respond to a cortical implant. The auditory cortex may only be a functional entrance into a larger parahippocampal based tinnitus network.

Modulation of gene expression in guinea pig paraflocculus after induction of hearing loss

Hearing loss often results in plastic changes in the central auditory pathways, which may be involved in the generation of tinnitus, a phantom auditory sensation. However, although animal studies have consistently shown increased neural activity in auditory structures after hearing loss, tinnitus does not always develop. It has therefore been suggested that non-auditory structures perform a gating or regulatory role that determines whether the increased activity in auditory structures leads to conscious perception. Recent evidence points to the paraflocculus of the cerebellum as having such a role. Therefore, we investigated the early effects of hearing loss on gene expression in guinea pig paraflocculus. Gene expression was investigated after two weeks recovery from either acoustic or mechanical cochlear trauma. The genes investigated in our study were associated with inhibitory neurotransmission (GABA-A receptor subunit alpha 1; glutamate decarboxylase 1), excitatory neurotransmission (glutamate receptor NMDA subunit 1), and regulation of transmitter release (member of RAB family of small GTPase). Our results show increased mRNA levels of glutamate decarboxylase 1 in ipsilateral paraflocculus with no difference between the different methods of cochlear trauma. Early modulation of gene expression in the paraflocculus suggests that an early effect of hearing loss may affect the influence of this structure on auditory processing.

Modulation of gene expression in guinea pig paraflocculus after induction of hearing loss

Hearing loss often results in plastic changes in the central auditory pathways, which may be involved in the generation of tinnitus, a phantom auditory sensation. However, although animal studies have consistently shown increased neural activity in auditory structures after hearing loss, tinnitus does not always develop. It has therefore been suggested that non-auditory structures perform a gating or regulatory role that determines whether the increased activity in auditory structures leads to conscious perception. Recent evidence points to the paraflocculus of the cerebellum as having such a role. Therefore, we investigated the early effects of hearing loss on gene expression in guinea pig paraflocculus. Gene expression was investigated after two weeks recovery from either acoustic or mechanical cochlear trauma. The genes investigated in our study were associated with inhibitory neurotransmission (GABA-A receptor subunit alpha 1; glutamate decarboxylase 1), excitatory neurotransmission (glutamate receptor NMDA subunit 1), and regulation of transmitter release (member of RAB family of small GTPase). Our results show increased mRNA levels of glutamate decarboxylase 1 in ipsilateral paraflocculus with no difference between the different methods of cochlear trauma. Early modulation of gene expression in the paraflocculus suggests that an early effect of hearing loss may affect the influence of this structure on auditory processing.

Combining Transcranial Direct Current Stimulation and Tailor-Made Notched Music Training to Decrease Tinnitus-Related Distress – A Pilot Study

The central auditory system has a crucial role in tinnitus generation and maintenance. Curative treatments for tinnitus do not yet exist. However, recent attempts in the therapeutic application of both acoustic stimulation/training procedures and electric/magnetic brain stimulation techniques have yielded promising results. Here, for the first time we combined tailor-made notched music training (TMNMT) with transcranial direct current stimulation (tDCS) in an effort to modulate TMNMT efficacy in the treatment of 32 patients with tonal tinnitus and without severe hearing loss. TMNMT is characterized by regular listening to so-called notched music, which is generated by digitally removing the frequency band of one octave width centered at the individual tinnitus frequency. TMNMT was applied for 10 subsequent days (2.5 hours of daily treatment). During the initial 5 days of treatment and the initial 30 minutes of TMNMT sessions, tDCS (current strength: 2 mA; anodal (N = 10) vs. cathodal (N = 11) vs. sham (N = 11) groups) was applied simultaneously. The active electrode was placed on the head surface over left auditory cortex; the reference electrode was put over right supra-orbital cortex. To evaluate treatment outcome, tinnitus-related distress and perceived tinnitus loudness were assessed using standardized tinnitus questionnaires and a visual analogue scale. The results showed a significant treatment effect reflected in the Tinnitus Handicap Questionnaire that was largest after 5 days of treatment. This effect remained significant at the end of follow-up 31 days after treatment cessation. Crucially, tDCS did not significantly modulate treatment efficacy - it did not make a difference whether anodal, cathodal, or sham tDCS was applied. Possible explanations for the findings and functional modifications of the experimental design for future studies (e.g. the selection of control conditions) are discussed.

The characteristics of Audioscan and DPOAE measures in tinnitus patients with normal hearing thresholds

Objectives: To investigate auditory dysfunction in patients with tinnitus and normal hearing thresholds using two sensitive audiological measures. Design: The study was designed to investigate the characteristics of Audioscan and DPOAE tests in tinnitus patients with normal hearing thresholds. Audioscan and DPOAE notches were analysed and compared. All tests were performed in a sound-treated chamber or in a sound-treated room. Study sample: Forty-five tinnitus patients with normal hearing thresholds were examined following a written clinical protocol. Results: The averaged hearing levels obtained from tinnitus participants were significantly worse at high frequencies than those derived from the normative data. There was a significantly higher prevalence of Audioscan and DPOAE notches, whose central frequencies matched tinnitus frequencies in the mid-frequency regions, but not in the low- and high-frequency regions. A significant correlation was found between the centre frequencies of the Audioscan notches and the DPOAE notches from 500 to 4000 Hz. Conclusion: Tinnitus in different frequency regions may be associated with different underlying mechanisms of tinnitus generation. Some negative results on the Audioscan and DPOAE notches matching tinnitus pitches may be due to a limited set of discrete frequencies used for the tinnitus pitch matching test.

Relation of distortion product otoacoustic emission and tinnitus in normal hearing patients: a pilot study.

Tinnitus, the perception of the sound in the absence of an external acoustic source, disrupts the daily life 1 out of every 200 adults, yet its physiological basis remains largely a mystery. The generation of tinnitus is commonly linked with the impaired functioning of the outer hair cells (OHC) inside the cochlea. Otoacoustic emissions are the objective test used to assess their activity. The objective of the investigation was to study the features of Distortion product OtoAcoustic emissions (DPOAE) in a group of tinnitus patients with normal hearing and to find out whether there is any difference in DPOAE findings in the tinnitus patients with normal hearing and in persons with normal hearing with no complaint of tinnitus. The participants consisted of two groups. The subject group consisted of 16 ears of patients, in which 6 subjects were having tinnitus in both ears while 4 subjects were having tinnitus only in one ear. All subjects were aged between 20 to 60 years with complaint of tinnitus with audiometrically normal hearing. Control group was comprised of 16 audiometrically normal hearing ears of persons who were age and gender matched with the subject groups and had no complaint of tinnitus. Both the subject group as well as control group was subjected for DPOAE test. Findings of both the groups were compared using the unpaired t test. It was observed that the amplitudes of DPOAE were significantly lower in tinnitus patients than that of persons without complaint of tinnitus, at a frequency of 1281-1560, 5120-6250, 7243-8837 Hz, which imply that decrease of DPOAEs amplitudes may be related to the presence of tinnitus. It can be concluded that there is association between tinnitus and reduced OHC activity which indicate the OHC of cochlea are involved in the generation of tinnitus.

Identifying Tinnitus‐Related Genes Based on a Side‐Effect Network Analysis

Tinnitus, phantom sound perception, is a worldwide highly prevalent disorder for which no clear underlying pathology has been established and for which no approved drug is on the market. Thus, there is an urgent need for new approaches to understand this condition. We used a network pharmacology side-effect analysis to search for genes that are involved in tinnitus generation. We analyzed a network of 1,313 drug–target pairs, based on 275 compounds that elicit tinnitus as side effect and their targets reported in databases, and used a quantitative score to identify emergent significant targets that were more common than expected at random. Cyclooxigenase 1 and 2 were significant, which validates our approach, since salicylate is a known tinnitus generator. More importantly, we predict previously unknown tinnitus-related targets. The present results have important implications toward understanding tinnitus pathophysiology and might pave the way toward the design of novel pharmacotherapies.

Playing and listening to tailor-made notched music: cortical plasticity induced by unimodal and multimodal training in tinnitus patients.

Background. The generation and maintenance of tinnitus are assumed to be based on maladaptive functional cortical reorganization. Listening to modified music, which contains no energy in the range of the individual tinnitus frequency, can inhibit the corresponding neuronal activity in the auditory cortex. Music making has been shown to be a powerful stimulator for brain plasticity, inducing changes in multiple sensory systems. Using magnetoencephalographic (MEG) and behavioral measurements we evaluated the cortical plasticity effects of two months of (a) active listening to (unisensory) versus (b) learning to play (multisensory) tailor-made notched music in nonmusician tinnitus patients. Taking into account the fact that uni- and multisensory trainings induce different patterns of cortical plasticity we hypothesized that these two protocols will have different affects. Results. Only the active listening (unisensory) group showed significant reduction of tinnitus related activity of the middle temporal cortex and an increase in the activity of a tinnitus-coping related posterior parietal area. Conclusions. These findings indicate that active listening to tailor-made notched music induces greater neuroplastic changes in the maladaptively reorganized cortical network of tinnitus patients while additional integration of other sensory modalities during training reduces these neuroplastic effects.

Is noise-induced cochlear neuropathy key to the generation of hyperacusis or tinnitus?

Perceptual abnormalities such as hyperacusis and tinnitus often occur after acoustic overexposure. Although such exposure can also result in permanent threshold elevation, some individuals with noise-induced hyperacusis or tinnitus show clinically normal thresholds. Recent work in animals has shown that a "neuropathic" noise exposure can cause immediate, permanent degeneration of the cochlear nerve despite complete threshold recovery and lack of hair cell damage (Kujawa SG, Liberman MC. J Neurosci 29: 14077-14085, 2009; Lin HW, Furman AC, Kujawa SG, Liberman MC. J Assoc Res Otolaryngol 12: 605-616, 2011). Here we ask whether this noise-induced primary neuronal degeneration results in abnormal auditory behavior, based on the acoustic startle response (ASR) and prepulse inhibition (PPI) of startle. Responses were measured in mice exposed either to a "neuropathic" noise or to a lower-intensity, "nonneuropathic" noise and in unexposed control mice. Mice with cochlear neuropathy displayed hyperresponsivity to sound, evidenced by enhanced ASR and PPI, while exposed mice without neuronal loss showed control-like responses. Gap PPI tests, often used to assess tinnitus, revealed limited gap detection deficits in mice with cochlear neuropathy only for certain gap-startle latencies, inconsistent with the presence of tinnitus "filling in the gap." Despite significantly reduced wave 1 of the auditory brainstem response, representing cochlear nerve activity, later peaks were unchanged or enhanced, suggesting compensatory neural hyperactivity in the auditory brainstem. Considering the rapid postexposure onset of both cochlear neuropathy and exaggerated startle-based behavior, the results suggest a role for cochlear primary neuronal degeneration, per se, in the central neural excitability that could underlie the generation of hyperacusis.