Neuroprotective Effect of Valproic Acid on Salicylate-Induced Tinnitus.

High-dose salicylate induces temporary moderate hearing loss and the perception of a high-pitched tinnitus in humans and animals. Previous studies demonstrated that high doses of salicylate increase N-methyl-d-aspartate (NMDA) receptor levels, resulting in a rise in Ca2+ influx and induction of excitotoxicity. Glutamate excitotoxicity is associated with failure in the maintenance of calcium homeostasis, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Valproic acid (VPA) is widely used for the management of bipolar disorder, epilepsy, and migraine headaches, and is known to regulate NMDA receptor activity. In this study, we examined the beneficial effects of VPA in a salicylate-induced tinnitus model in vitro and in vivo. Cells were pretreated with VPA followed by salicylate treatment. The expression levels of NMDA receptor subunit NR2B, phosphorylated cAMP response element-binding protein-an apoptosis marker, and intracellular levels of ROS were measured using several biochemical techniques. We observed increased expression of NR2B and its related genes TNFα and ARC, increased intracellular ROS levels, and induced expression of cleaved caspase-3. These salicylate-induced changes were attenuated in the neuronal cell line SH-SY5Y and rat cortical neurons after VPA pretreatment. Together, these results provide evidence of the beneficial effects of VPA in a salicylate-induced temporary hearing loss and tinnitus model.

Blast-induced tinnitus: Animal models.

Blast-induced tinnitus is a prevalent problem among military personnel and veterans, as blast-related trauma damages the vulnerable microstructures within the cochlea, impacts auditory and non-auditory brain structures, and causes tinnitus and other disorders. Thus far, there is no effective treatment of blast-induced tinnitus due to an incomplete understanding of its underlying mechanisms, necessitating development of reliable animal models. This article focuses on recent animal studies using behavioral, electrophysiological, imaging, and pharmacological tools. The mechanisms underlying blast-induced tinnitus are largely similar to those underlying noise-induced tinnitus: increased spontaneous firing rates, bursting, and neurosynchrony, Mn++ accumulation, and elevated excitatory synaptic transmission. The differences mainly lie in the data variability and time course. Noise trauma-induced tinnitus mainly originates from direct peripheral deafferentation at the cochlea, and its etiology subsequently develops along the ascending auditory pathways. Blast trauma-induced tinnitus, on the other hand, results from simultaneous impact on both the peripheral and central auditory systems, and the resultant maladaptive neuroplasticity may also be related to the additional traumatic brain injury. Consequently, the neural correlates of blast-induced tinnitus have different time courses and less uniform manifestations of its neural correlates.

Changes in tinnitus and physiological biomarkers of stress in response to short-term broadband noise and sounds of nature.

BACKGROUND: Tinnitus is the perception of sound when no external sound source is present. In some cases, this perception coincides with, or results in, stress. Tinnitus-related distress has been associated with increased levels of cortisol and elevated levels of sympathetic tone. Our primary hypothesis was that short-term sound exposure would reduce tinnitus perception and various physiological measures of stress. A secondary hypothesis was that a self-selected nature sound would reduce physiological markers of stress more than broadband noise. METHODS: Twenty-one participants with constant bothersome tinnitus underwent an audiological assessment. Measurements of blood pressure, heart rate, salivary cortisol and cortisone concentrations, and tinnitus ratings were carried out three times: prior to and, in a counterbalance order, after 30 min of broadband noise and after 30 min of a self-selected nature sound (from: ocean waves, stream, rain or shower sounds). RESULTS: Findings revealed significant reductions in blood pressure measurements following broadband noise. None of the other stress measures demonstrated a statistically significant change. Both broadband noise and nature sounds elicited significant improvements in ratings of tinnitus. CONCLUSIONS: While both sound types had a positive impact on many dimensions of tinnitus, only the broadband noise was associated with a reduction in blood pressure. These results are consistent with a complex interaction between sound and tinnitus and suggest a multifactorial basis to sound therapy that includes a reduction in arousal.

[Effect of electrical stimulation at auricular points combined with sound masking on the expression of CREB, BDNF and TrkB in the auditory cortex of tinnitus rats].

OBJECTIVE: To explore the effect of electrical stimulation at auricular points (EAS) combined with sound masking on the expression of cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) in the auditory cortex of tinnitus rats. METHODS: A total of 27 adult male SD rats were randomly divided into a control group, a model group and an EAS group. The rats in the model group and the EAS group were intervened with intraperitoneal injection of sodium salicylate to induce tinnitus model, while the rats in the control group were intervened with injection of 0.9% NaCl solution. After the model was successfully established, the rats in the EAS group were treated with electrical stimulation at "Shenmen" (TF4) and "Yidan" (CO11), combined with sound masking; the treatment was given once a day for 15 days. The gap prepulse inhibition of acoustic startle (GPIAS) and prepulse inhibition (PPI) testing were performed using the acoustic startle reflex starter package for rats. The expression of BDNF, TrkB, CREB and p-CREB in the auditory cortex of each group were measured with Western Blot analysis. RESULTS: ① Compared with the control group, the GPIAS values in 12 kHz, 16 kHz, 20 kHz and 28 kHz were significantly decreased in the model group (all P<0.05); compared with the model group, GPIAS values in 12 kHz, 16 kHz, 20 kHz and 28 kHz were significantly increased in the EAS group (all P<0.05). ② Compared with the control group, the expression of BDNF and p-CREB in the model group was significantly increased (P<0.01), and the expression of TrkB in the model group was significantly increased (P<0.05); the differences of expression of BDNF, TrkB, CREB and p-CREB between the model group and the EAS group had no statistics significance (all P>0.05). CONCLUSION: EAS could improve the GPIAS values of high-frequency background sound in tinnitus rats, which may be related with the upregulation of the BDNF/TrkB/CREB signaling pathway in the auditory cortex, leading to the reversion of the maladaptive plasticity.

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs.

Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap-prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude-intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2-weeks following noise-exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20-60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus-specific changes were particularly prominent in hippocampal synapse-rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus-specific changes occurred in synapse-rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus.

Bone Metabolic Markers in the Clinical Assessment of Patients with Superior Semicircular Canal Dehiscence.

BACKGROUND: Superior semicircular canal dehiscence (SSCD) is a bony defect in the osseous shell of the petrous temporal bone. The pathophysiological association between osteoporosis and SSCD remains poorly understood. We investigated the relationship between bone metabolic markers and symptoms in patients with SSCD. METHODS: We collected patient demographics and clinical parameters for adult patients diagnosed with SSCD on high-resolution computed tomography scans. We used point-biserial correlation analysis to investigate the relationship between bone metabolic markers and symptoms in patients with SSCD. We compared clinical symptoms before and after surgical repair of SSCD through a middle fossa craniotomy using McNemar's test for paired comparisons of binary measures. RESULTS: We included a total of 99 patients (64 females and 35 males; average age 52 years; 118 surgeries). The level of serum calcium correlated with the need for a second surgery (rpb = -0.35, P = 0.001). Postoperative calcium supplementation negatively correlated with improvement in dizziness (rpb = -0.36, P = 0.01). The level of 25-hydroxyvitamin D correlated with preoperative hyperacusis (rpb = -0.98, P = 0.02) and postoperative autophony (rpb = 0.96, P = 0.04). Postoperative vitamin D supplementation positively correlated with hearing decline (rpb = 0.04, P = 0.04) The level of thyroid stimulating hormone correlated with preoperative autophony, amplification, and tinnitus (rpb = -0.71, rpb = -0.75, rpb = -0.70, all P < 0.001). CONCLUSIONS: Bone metabolic markers could be important in the clinical assessment of SSCD patients and could be potential targets for symptom management.

Effects of the cannabinoid CB1 agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs.

Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2'-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6-10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis.

Salicylate-induced frequency-map reorganization in four subfields of the mouse auditory cortex.

Salicylate is the active ingredient in aspirin, and in high-doses it is used as an experimental tool to induce transient hearing loss, tinnitus, and hyperacusis. These salicylate-induced perceptual disturbances are associated with tonotopic-map reorganization and neural activity modulation, and such neural correlates have been examined in the central auditory pathway, including the auditory cortex (AC). Although previous studies have reported that salicylate induces increases in noise-burst-evoked neural responses and reorganization of tonotopic maps in the primary AC, little is known about the effects of salicylate on other frequency-organized AC subfields such as the anterior auditory, secondary auditory, and dorsomedial fields. Therefore, to examine salicylate-induced spatiotemporal effects on AC subfields, we measured sound-evoked neural activity in mice before and after the administration of sodium salicylate (SS, 200 mg/kg), using flavoprotein auto-fluorescence imaging. SS-treatment gradually reduced responses driven by tone-bursts with lower (≤8 kHz) and higher (≥25 kHz) frequencies over 3 h, whereas evoked responses to tone-bursts within middle-range frequencies (e.g., 12 and 16 kHz) were sustained and unchanged in the four subfields. Additionally, in each of the four subfields, SS-treatment induced similar reorganization of tonotopic maps, and the response areas selectively driven by the middle-range frequencies were profoundly expanded. Our results indicate that the SS-induced tonotopic map reorganizations in each of the four AC subfields were similar, and only the extent of the activated areas responsive to tone-bursts with specific frequencies was subfield-dependent. Thus, we expect that examining cortical reorganization induced by SS may open the possibility of new treatments aimed at altering cortical reorganization into the normative functional organization.

The effects of repetitive transcranial magnetic stimulation in an animal model of tinnitus.

Tinnitus (phantom auditory perception associated with hearing loss) can seriously affect wellbeing. Its neural substrate is unknown however it has been linked with abnormal activity in auditory pathways. Though no cure currently exists, repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce tinnitus in some patients, possibly via induction of cortical plasticity involving brain derived neurotrophic factor (BDNF). We examined whether low intensity rTMS (LI-rTMS) alleviates signs of tinnitus in a guinea pig model and whether this involves changes in BDNF expression and hyperactivity in inferior colliculus. Acoustic trauma was used to evoke hearing loss, central hyperactivity and tinnitus. When animals developed tinnitus, treatment commenced (10 sessions of 10 minutes 1 Hz LI-rTMS or sham over auditory cortex over 14 days). After treatment ceased animals were tested for tinnitus, underwent single-neuron recordings in inferior colliculus to assess hyperactivity and samples from cortex and inferior colliculus were taken for BDNF ELISA. Analysis revealed a significant reduction of tinnitus after LI-rTMS compared to sham, without a statistical significant effect on BDNF levels or hyperactivity. This suggests that LI-rTMS alleviates behavioural signs of tinnitus by a mechanism independent of inferior colliculus hyperactivity and BDNF levels and opens novel therapeutic avenues for tinnitus treatment.

Human Auditory and Adjacent Nonauditory Cerebral Cortices Are Hypermetabolic in Tinnitus as Measured by Functional Near-Infrared Spectroscopy (fNIRS).

Tinnitus is the phantom perception of sound in the absence of an acoustic stimulus. To date, the purported neural correlates of tinnitus from animal models have not been adequately characterized with translational technology in the human brain. The aim of the present study was to measure changes in oxy-hemoglobin concentration from regions of interest (ROI; auditory cortex) and non-ROI (adjacent nonauditory cortices) during auditory stimulation and silence in participants with subjective tinnitus appreciated equally in both ears and in nontinnitus controls using functional near-infrared spectroscopy (fNIRS). Control and tinnitus participants with normal/near-normal hearing were tested during a passive auditory task. Hemodynamic activity was monitored over ROI and non-ROI under episodic periods of auditory stimulation with 750 or 8000 Hz tones, broadband noise, and silence. During periods of silence, tinnitus participants maintained increased hemodynamic responses in ROI, while a significant deactivation was seen in controls. Interestingly, non-ROI activity was also increased in the tinnitus group as compared to controls during silence. The present results demonstrate that both auditory and select nonauditory cortices have elevated hemodynamic activity in participants with tinnitus in the absence of an external auditory stimulus, a finding that may reflect basic science neural correlates of tinnitus that ultimately contribute to phantom sound perception.

Specific activation of operculum 3 (OP3) brain region during provoked tinnitus-related phantom auditory perceptions in humans.

The phantom sound perception mechanism by which a sound perception occurs without any external sound source is still enigmatic. According to our previous fMRI study, a small region in the parietal operculum 3 was hyperactivated as a function of tinnitus periodicity in subjects with acoustic trauma tinnitus sequelae. This region was localized in the vicinity of neural correlates of middle-ear tympano-ossicular chain movements due to pressure variations. Disturbed proprioceptors are known to trigger illusory perceptions; therefore, we hypothesized that a disturbance of middle-ear proprioceptors may originate phantom sound perceptions. We designed an fMRI study that aimed to stimulate middle-ear proprioceptors by repetitive vibrations using various rates of click trains. In this study, we report that exposure to specific rates of stimuli for a few minutes at comfortable intensity level in healthy subjects distinctly triggered transient tinnitus-like aftereffects. The fMRI neural correlates of the aftereffects were unequivocally localized in the same parietal region as in acoustic trauma tinnitus sufferers. Our results strongly suggest that a middle-ear kinesthetic/proprioceptive illusion exists at the origin of acoustic trauma tinnitus via a somatosensory pathway encompassing the trigeminal system.

Monosialotetrahexosylganglioside Inhibits the Expression of p-CREB and NR2B in the Auditory Cortex in Rats with Salicylate-Induced Tinnitus.

BACKGROUND: This study investigated the effects of monosialotetrahexosylganglioside (GM1) on the expression of N-methyl-D-aspartate receptor subunit 2B (NR2B) and phosphorylated (p)-cyclic AMP response element-binding protein (CREB) in the auditory cortex of rats with tinnitus. METHODS: Tinnitus-like behavior in rats was tested with the gap prepulse inhibition of acoustic startle paradigm. We then investigated the NR2B mRNA and protein and p-CREB protein levels in the auditory cortex of tinnitus rats compared with normal rats. RESULTS: Rats treated for 4 days with salicylate exhibited tinnitus. NR2B mRNA and protein and p-CREB protein levels were upregulated in these animals, with expression returning to normal levels 14 days after cessation of treatment; baseline levels of NR2B and p-CREB were also restored by GM1 administration. CONCLUSIONS: These data suggest that chronic salicylate administration induces tinnitus via upregulation of p-CREB and NR2B expression, and that GM1 can potentially be used to treat tinnitus.

Expression of Antioxidant Genes in the Mouse Cochlea and Brain in Salicylate-Induced Tinnitus and Effect of Treatment with Spirulina platensis Water Extract.

Salicylate increased manganese-superoxide dismutase (Mn-SOD) gene expression, but decreased catalase (CAT) gene expression in the cochlea and various brain regions of mice with tinnitus. Spirulinaplatensis water extract reduced salicylate-induced overexpression of the Mn-SOD gene, but increased salicylate-induced downregulation of the CAT gene. With the exception of significantly increased SOD activity in the brainstem and inferior colliculus of the Spirulina group, SOD and CAT enzyme activities did not differ among the three groups. The tinnitus group had higher malondialdehyde (MDA) levels than the control group in the temporal and the frontal lobes. S.platensis water extract reduced salicylate-induced elevations of MDA levels in many brain areas. We proposed that altered expression of antioxidant genes may reflect states of oxidative stress associated with tinnitus.

Using prophylactic antioxidants to prevent noise-induced hearing damage in young adults: a protocol for a double-blind, randomized controlled trial.

BACKGROUND: During leisure activities young people are often exposed to excessive noise levels resulting in an increase of noise-induced symptoms such as hearing loss, tinnitus and hyperacusis. Noise-induced tinnitus is often perceived after loud music exposure and provides an important marker for overexposure as a temporary threshold shift that is often not experienced by the individual itself. As oxidative stress plays an important role in the pathogenesis of noise-induced hearing loss, the use of antioxidants to prevent hearing damage has recently become the subject of research. METHODS: This study proposes a randomized, double-blind, placebo-controlled crossover trial to assess the effects of a prophylactic combination of N-acetylcysteine (600 mg) and magnesium (200 mg) prior to leisure noise exposure in young adults. The primary outcome measure is the tinnitus loudness scored by a visual analogue scale (VAS). Secondary outcome measures are the differences in audiological measurements for the antioxidant treatments compared to placebo intake. Audiological testing comprising of pure tone audiometry including frequencies up to 16 kHz, distortion product otoacoustic emissions, transient-evoked otoacoustic emissions and speech-in-noise testing will be performed prior to and within 7 hours after noise exposure. By use of a mixed effects statistical model, the effects of antioxidants compared to placebo intake will be assessed. DISCUSSION: As adolescents and young adults often do not use hearing protection while being exposed to loud music, the use of preventive antioxidant intake may provide a useful and harmless way to prevent noise-induced hearing damage in this population. Furthermore, when exposed to hazardous noise levels the protection provided by hearing protectors might not be sufficient to prevent hearing damage and antioxidants may provide additive otoprotective effects. Previous research mainly focused on occupational noise exposure. The present study provides a protocol to assess the usefulness of antioxidants during leisure noise activities. TRIAL REGISTRATION: The present protocol is registered at ClinicalTrials.gov: NCT01727492.

Effects of early and late treatment with L-baclofen on the development and maintenance of tinnitus caused by acoustic trauma in rats.

Subjective tinnitus is a chronic neurological disorder in which phantom sounds are perceived. Recent evidence supports the hypothesis that tinnitus is related to neuronal hyperactivity in auditory brain regions, and consequently drugs that increase GABAergic neurotransmission in the CNS, such as the GABA(B) receptor agonist L-baclofen, may be effective as a treatment. The aim of this study was to investigate the effects of early (5 mg/kg s.c., 30 min and then every 24 h for 5 days following noise exposure) and late treatment (3 mg/kg/day s.c. for 4.5 weeks starting at 17.5 weeks following noise exposure) with l-baclofen on the psychophysical attributes of tinnitus in a conditioned lick suppression model following acoustic trauma in rats. Acoustic trauma (a 16-kHz, 115-dB pure tone presented unilaterally for 1h) resulted in a significant decrease in the suppression ratio (SR) compared to sham controls in response to 20-kHz tones at 2, 10 and 17.5 weeks post-exposure (P ≤ 0.009, P ≤ 0.02 and P ≤ 0.03, respectively). However, l-baclofen failed to prevent the development of tinnitus when administered during the first 5 days following the acoustic trauma and also failed to reverse it when treatment was carried out every day for 4.5 weeks. We also found that treatment with L-baclofen did not alter the expression of the GABA(B)-R2 subunit in the cochlear nucleus of noise-exposed animals.

Noise-induced inner hair cell ribbon loss disturbs central arc mobilization: a novel molecular paradigm for understanding tinnitus.

Increasing evidence shows that hearing loss is a risk factor for tinnitus and hyperacusis. Although both often coincide, a causal relationship between tinnitus and hyperacusis has not been shown. Currently, tinnitus and hyperacusis are assumed to be caused by elevated responsiveness in subcortical circuits. We examined both the impact of different degrees of cochlear damage and the influence of stress priming on tinnitus induction. We used (1) a behavioral animal model for tinnitus designed to minimize stress, (2) ribbon synapses in inner hair cells (IHCs) as a measure for deafferentation, (3) the integrity of auditory brainstem responses (ABR) to detect differences in stimulus-evoked neuronal activity, (4) the expression of the activity-regulated cytoskeletal protein, Arc, to identify long-lasting changes in network activity within the basolateral amygdala (BLA), hippocampal CA1, and auditory cortex (AC), and (5) stress priming to investigate the influence of corticosteroid on trauma-induced brain responses. We observed that IHC ribbon loss (deafferentation) leads to tinnitus when ABR functions remain reduced and Arc is not mobilized in the hippocampal CA1 and AC. If, however, ABR waves are functionally restored and Arc is mobilized, tinnitus does not occur. Both central response patterns were found to be independent of a profound threshold loss and could be shifted by the corticosterone level at the time of trauma. We, therefore, discuss the findings in the context of a history of stress that can trigger either an adaptive or nonadaptive brain response following injury.

Emerging pharmacotherapy of tinnitus.

One in ten adults has clinically significant subjective tinnitus, and for one in hundred, tinnitus severely affects their quality of life. Despite the significant unmet clinical need for a safe and effective drug targeting tinnitus relief, there is currently not a single FDA-approved drug on the market. Even a drug that produces a small but significant effect would have a huge therapeutic impact. In the last few years, there have been significant advances in i) the understanding of the pathophysiology of the different forms of tinnitus, ii) the establishment of valid animal models and iii) the development of clinical trial methodology. A glimpse of hope is appearing in the horizon as an increasing number of pharmaceutical industries now have compounds targeting tinnitus in their pipeline.

Cochlear NMDA receptor blockade prevents salicylate-induced tinnitus.

Large doses of aspirin produce reversible hearing loss and tinnitus. These effects have been attributed to the salicylate ion, the active component of aspirin. Salicylate acts as a competitive antagonist at the anion-binding site of prestin, the motor protein of sensory outer hair cells. This provides an explanation for the hearing loss induced by aspirin. However, the molecular mechanism of salicylate-induced tinnitus remains obscure. One physiological explanation is that salicylate ototoxicity is likely to originate in an alteration to arachidonic acid metabolism. Arachidonic acid potentiates NMDA receptor currents. We therefore tested the involvement of cochlear NMDA receptors in the occurrence of tinnitus. Tinnitus was assessed with a behavioural test based on an active avoidance paradigm. Results showed that the tinnitus induced by salicylate may be suppressed by the introduction of NMDA antagonists into the cochlear fluids. To determine if the activation of NMDA receptors was linked to cyclooxygenase inhibition, we investigated the effect of mefenamate (a potent cyclooxygenase inhibitor). Since NMDA antagonists also blocked mefenamate-induced tinnitus, we suggest that salicylate-induced tinnitus is mediated by cochlear NMDA receptors through the inhibition of cyclooxygenase activity. Target cochlear NMDA receptors may therefore present a therapeutic strategy for the treatment of tinnitus.

Evidence for tinnitus-related plasticity in the auditory and limbic system, demonstrated by arg3.1 and c-fos immunocytochemistry.

Distributions of arg3.1 and c-fos immunoreactive neurons (IRN) in gerbil auditory cortex (AC) and amygdala showed characteristic differences when comparing systemic application of the tinnitus-eliciting drug salicylate with acoustic stimulation or saline injections. In AC, arg3.1 IRN induced by stimulation focused in regions corresponding to the frequency content of the stimulus. Injections of salicylate (350 mg/kg body weight) led to accumulation of arg3.1 IRN in the high frequency domain, while saline injections produced a diffuse distribution. After all treatments, c-fos IRN outnumbered arg3.1 IRN in AC and showed a broad distribution. In subcortical auditory structures arg3.1 IRN were absent in all but one brain. In ventral cochlear nucleus, c-fos IRN were always found after stimulation and often also after saline injections, whereas none were present when injecting salicylate. Similarly, in inferior colliculus, numbers of c-fos IRN were lowest after salicylate injections. In the amygdala, c-fos and arg3.1 IRN were increased substantially after salicylate injections compared to auditory stimulation or saline injections. In particular in its central nucleus, c-fos and arg3.1 IRN were found exclusively after the tinnitus-inducing treatment, suggesting that coactivation of the AC and the amygdala may by an essential feature of tinnitus-related activation.

Ultra-high-frequency acoustic stimulation and tinnitus control: a positron emission tomography study.

Ultra-high-frequency (UHF) external acoustic stimulation with the UltraQuiet device (UQ) has been reported to provide significant relief of severe disabling-type tinnitus. The nuclear medicine imaging technique of positron emission tomography (PET) was selected as a monitoring system to compare objectively metabolic alterations in brain function before and after UHF/UQ and to correlate the PET data with the subjective behavioral response of patients reporting tinnitus relief. PET of brain was completed on 6 patients randomly selected from a cohort of 15 patients included in a protocol to establish long-term tinnitus relief with UHF/UQ. Twelve specific regions of interest (ROI) were selected for PET of brain examination on the basis of results obtained with single-photon emission computed tomography (SPECT) of brain examinations recommended for patients with severe disabling-type tinnitus and demonstrating significant perfusion asymmetries in the right and left brain ROI of the primary auditory cortex; frontal, temporal, parietal, and medial temporal lobes; and cerebellum. PET of brain results included ratios of post- and pre-UHF/UQ stimulation that demonstrated no random response in the selected PET of brain ROI and ratios of post- and pre-UHF/UQ stimulation that demonstrated three categories of response in the selected PET brain ROI for all six patients: hypermetabolism in three patients; hypometabolism in two; and a mixed response in one. Correlation was established for each patient among PET and electrophysiological responses of alteration in minimal masking levels, the residual UHF neuronal response as reflected in the UHF audiogram, and the subjective reported behavioral responses of patients (obtained from outcome questionnaires for tinnitus relief, which focused on tinnitus intensity, annoyance, severity index, and a subjective scale of value of the UHF/UQ device for tinnitus relief. The subjective behavioral response for tinnitus relief with UHF/UQ was found to reflect a dual effect: acoustic stimulation of the residual neuronal function in the UHF range (10-14 kHz) and audiometric thresholds of 40-50 dB sound pressure level (SPL), and the metabolic activity at brain cortex for neuronal reprogramming. The PET of brain categories of response suggested that the UHF/UQ "masking" is predominantly reflective of neuronal reprogramming at the brain cortex. Nuclear medicine PET of brain imaging has provided an objective monitoring system for attempting to establish the efficacy of UHF/UQ for tinnitus relief. No complication of the tinnitus was reported secondary to the PET of brain examination. This limited PET of brain study supports the clinical recommendation of the efficacy of UHF/UQ external acoustic stimulation for a selected population of patients with tinnitus of the severe disabling type.