Review: Neural Mechanisms of Tinnitus and Hyperacusis in Acute Drug-Induced Ototoxicity.

Purpose Tinnitus and hyperacusis are debilitating conditions often associated with age-, noise-, and drug-induced hearing loss. Because of their subjective nature, the neural mechanisms that give rise to tinnitus and hyperacusis are poorly understood. Over the past few decades, considerable progress has been made in deciphering the biological bases for these disorders using animal models. Method Important advances in understanding the biological bases of tinnitus and hyperacusis have come from studies in which tinnitus and hyperacusis are consistently induced with a high dose of salicylate, the active ingredient in aspirin. Results Salicylate induced a transient hearing loss characterized by a reduction in otoacoustic emissions, a moderate cochlear threshold shift, and a large reduction in the neural output of the cochlea. As the weak cochlear neural signals were relayed up the auditory pathway, they were progressively amplified so that the suprathreshold neural responses in the auditory cortex were much larger than normal. Excessive central gain (neural amplification), presumably resulting from diminished inhibition, is believed to contribute to hyperacusis and tinnitus. Salicylate also increased corticosterone stress hormone levels. Functional imaging studies indicated that salicylate increased spontaneous activity and enhanced functional connectivity between structures in the central auditory pathway and regions of the brain associated with arousal (reticular formation), emotion (amygdala), memory/spatial navigation (hippocampus), motor planning (cerebellum), and motor control (caudate/putamen). Conclusion These results suggest that tinnitus and hyperacusis arise from aberrant neural signaling in a complex neural network that includes both auditory and nonauditory structures.

Functional Neuroanatomy of Salicylate- and Noise-Induced Tinnitus and Hyperacusis.

Tinnitus and hyperacusis are debilitating conditions often associated with aging or exposure to intense noise or ototoxic drugs. One of the most reliable methods of inducing tinnitus is with high doses of sodium salicylate, the active ingredient in aspirin. High doses of salicylate have been widely used to investigate the functional neuroanatomy of tinnitus and hyperacusis. High doses of salicylate have been used to develop novel behavioral methods to detect the presence of tinnitus and hyperacusis in animal models. Salicylate typically induces a hearing loss of approximately 20 dB which greatly reduces the neural output of the cochlea. As this weak neural signal emerging from the cochlea is sequentially relayed to the cochlear nucleus, inferior colliculus, medial geniculate, and auditory cortex, the neural response to suprathreshold sounds is progressively amplified by a factor of 2-3 by the time the signal reaches the auditory cortex, a phenomenon referred to as enhanced central gain. Sound-evoked hyperactivity also occurred in the amygdala, a region that assigns emotional significance to sensory stimuli. Resting state functional magnetic imaging of the BOLD signal revealed salicylate-induced increases in spontaneous neural activity in the inferior colliculus, medial geniculate body, and auditory cortex as well as in non-auditory areas such as the amygdala, reticular formation, cerebellum, and other sensory areas. Functional connectivity of the BOLD signal revealed increased neural coupling between several auditory areas and non-auditory areas such as the amygdala, cerebellum, reticular formation, hippocampus, and caudate/putamen; these strengthened connections likely contribute to the multifaceted dimensions of tinnitus. Taken together, these results suggest that salicylate-induced tinnitus disrupts a complex neural network involving many auditory centers as well as brain regions involved with emotion, arousal, memory, and motor planning. These extra-auditory centers embellish the basic auditory percepts that results in tinnitus and which may also contribute to hyperacusis.

Auditory Brainstem Changes in Timing may Underlie Hyperacusis in a Salicylate-induced Acute Rat Model.

Hyperacusis, an exaggerated, sometimes painful perception of loudness even for soft sounds, is a poorly understood distressing condition. While the involvement of modified gain of central auditory neurons and the influence of nonauditory brain regions are well-documented, the issue of where in the auditory system these abnormalities arise remains open, particularly when hyperacusis comes without sensorineural hearing loss. Here we used acute intraperitoneal administration of sodium salicylate (150 mg/kg) in rats, enough to produce > 10-dB decrease in acoustic startle threshold with mild hearing loss at low frequencies (<10 kHz). Anesthesia, necessary for middle-ear-reflex (MEMR) threshold measurements, abolished the olivocochlear efferent reflex but not the MEMR acting on frequencies < 10 kHz, and its mean threshold increased from 55 dB SPL in controls to 80 dB SPL in salicylate-treated animals 60-90 minutes after injection, with an about 3-dB increase in acoustic energy reaching the cochlea. The mean latencies of auditory brainstem-evoked responses (ABR) conspicuously decreased after salicylate, by 0.25 millisecond at 6 kHz at every level, a frequency-dependent effect absent above 12 kHz. A generic model of loudness based upon cross-frequency coincidence detection predicts that with such timing changes, a transient sound may seem as loud at <40 dB SPL as it does in controls at >60 dB SPL. Candidate circuits able to act at the same time on the startle reflex, the MEMR and ABRs may be serotoninergic, as salicylate is known to increase brain serotonin and 5-HT neurons participate in MEMR and ABR circuits.

Does 5, 7-Dihydroxytryptamine injection into nucleus accumbens cause hyperacusis?

Hyperacusis may be defined as diminishing tolerance to moderate and high intensity sounds in people with normal hearing sensitivity. Serotonin plays a critical role in some of auditory tasks including startle reflex and prepulse inhibition. Serotonin deficiency can cause some diseases which can coincide with hyperacusis. The aim of the present study was to investigate the probable influence of serotonergic depletion in nucleus accumbens (NAcc) on the startle reflex. The startle reflexes were examined in Wistar rats (n: 48) in different intensities with and without the background noise. The amplitude of startle reflex significantly increased in NAcc-injected rats without background noise, while this difference disappeared in the presence of background noise in all intensities. These data proposed that the injection of 5, 7-Dihydroxytryptamine (5, 7-DHT) into nucleus accumbens will cause hyperacusis-like behavior, and strengthens the possibility of the role of serotonin and nucleus accumbens in hyperacusis.

Efficacy and safety of DFN-11 (sumatriptan injection, 3 mg) in adults with episodic migraine: an 8-week open-label extension study.

BACKGROUND: DFN-11, a 3 mg sumatriptan subcutaneous (SC) autoinjector for acute treatment of migraine, has not been assessed previously in multiple attacks. The objective of this study was to evaluate the efficacy, tolerability, and safety of DFN-11 in the acute treatment of multiple migraine attacks. METHODS: This was an 8-week open-label extension of multicenter, randomized, double-blind, placebo-controlled US study. Subjects averaging 2 to 6 episodic migraine attacks per month were randomized to DFN-11 or placebo to treat a single attack of moderate-to-severe intensity and then entered the extension study to assess the efficacy, tolerability, and safety of DFN-11 in multiple attacks of any pain intensity. RESULTS: Overall, 234 subjects enrolled in the open-label period, and 29 (12.4%) discontinued early. A total of 848 migraine episodes were treated with 1042 doses of open-label DFN-11 and subjects treated a mean (SD) of 3.9 (2.3) attacks. At 2 h postdose in attacks 1 (N = 216), 2 (N = 186), 3 (N = 142) and 4 (N = 110), respectively, pain freedom rates were 57.6%, 64.6%, 61.6%, and 66.3%; pain relief rates were 83.4%, 88.4%, 84.1%, and 81.7%; most bothersome symptom (MBS)-free rates were 69.0%, 76.5%, 77.7%, and 74.7%; nausea-free rates were 78.1%, 84.6%, 86.5%, and 85.7%; photophobia-free rates were 75.3%, 76.4%, 72.3%, and 77.5%; and phonophobia-free rates were 75.2%, 77.5%, 73.6%, and 76.0%. Overall, 40.6% (89/219) of subjects reported treatment-emergent adverse events (TEAE), the most common of which were associated with the injection site: swelling (12.8%), pain (11.4%), irritation (6.4%), and bruising (6.4%). Most subjects (65.2%, 58/89) had mild TEAEs; severe TEAEs were reported by 1 subject (treatment-related jaw tightness). Five subjects (2.1%) discontinued due to adverse events, which included mild throat tightness (n = 2), moderate hernia pain (n = 1), moderate hypersensitivity (n = 1), and 1 subject with mild nausea and moderate injection site swelling. There were no serious TEAEs and no new or unexpected safety findings. CONCLUSION: DFN-11 was effective, tolerable, and safe in the acute treatment of 4 migraine attacks over 8 weeks, with consistent responses on pain and associated symptoms. Most TEAEs were mild, with a very low incidence of triptan-related TEAEs. DFN-11 is potentially an effective and safe alternative for the acute treatment of migraine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02569853 . Registered 07 October 2015.

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 hyperacusis in rats: Dose- and frequency-dependent effects.

The use of auditory reaction time is a reliable measure of loudness perception in both animals and humans with reaction times (RT) decreasing with increasing stimulus intensity. Since abnormal loudness perception is a common feature of hyperacusis, a potentially debilitating auditory disorder in which moderate-intensity sounds are perceived as uncomfortable or painfully loud, we used RT measures to assess rats for salicylate-induced hyperacusis. A previous study using an operant conditioning RT procedure found that high-dose sodium salicylate (SS) induced hyperacusis-like behavior, i.e., faster than normal RTs to moderate and high level sounds, when rats were tested with broadband noise stimuli. However, it was not clear from that study if salicylate induces hyperacusis-like behavior in a dose- or frequency-dependent manner. Therefore, the goals of the current study were to determine how RT-intensity functions were altered by different doses of salicylate, and, using tone bursts, to determine if salicylate induces hyperacusis-like behavior across the entire frequency spectrum or only at certain frequencies. Similar to previous physiological studies, we began to see faster than normal RTs for sounds 60 dB SPL and greater with salicylate doses of 150 mg/kg and higher; indicating the rats were experiencing hyperacusis at high salicylate doses. In addition, high-dose salicylate significantly reduced RTs across all stimulus frequencies tested which suggests that a central neural excitability mechanism may be a potential driver of salicylate-induced changes in loudness perception and hyperacusis.

Tinnitus and hyperacusis: Contributions of paraflocculus, reticular formation and stress.

Tinnitus and hyperacusis are common and potentially serious hearing disorders associated with noise-, age- or drug-induced hearing loss. Accumulating evidence suggests that tinnitus and hyperacusis are linked to excessive neural activity in a distributed brain network that not only includes the central auditory pathway, but also brain regions involved in arousal, emotion, stress and motor control. Here we examine electrophysiological changes in two novel non-auditory areas implicated in tinnitus and hyperacusis: the caudal pontine reticular nucleus (PnC), involved in arousal, and the paraflocculus lobe of the cerebellum (PFL), implicated in head-eye coordination and gating tinnitus and we measure the changes in corticosterone stress hormone levels. Using the salicylate-induced model of tinnitus and hyperacusis, we found that long-latency (>10 ms) sound-evoked response components in both the brain regions were significantly enhanced after salicylate administration, while the short-latency responses were reduced, likely reflecting cochlear hearing loss. These results are consistent with the central gain model of tinnitus and hyperacusis, which proposes that these disorders arise from the amplification of neural activity in central auditory pathway plus other regions linked to arousal, emotion, tinnitus gating and motor control. Finally, we demonstrate that salicylate results in an increase in corticosterone level in a dose-dependent manner consistent with the notion that stress may interact with hearing loss in tinnitus and hyperacusis development. This increased stress response has the potential to have wide-ranging effects on the central nervous system and may therefore contribute to brain-wide changes in neural activity.

Tinnitus and hyperacusis involve hyperactivity and enhanced connectivity in auditory-limbic-arousal-cerebellar network.

Hearing loss often triggers an inescapable buzz (tinnitus) and causes everyday sounds to become intolerably loud (hyperacusis), but exactly where and how this occurs in the brain is unknown. To identify the neural substrate for these debilitating disorders, we induced both tinnitus and hyperacusis with an ototoxic drug (salicylate) and used behavioral, electrophysiological, and functional magnetic resonance imaging (fMRI) techniques to identify the tinnitus-hyperacusis network. Salicylate depressed the neural output of the cochlea, but vigorously amplified sound-evoked neural responses in the amygdala, medial geniculate, and auditory cortex. Resting-state fMRI revealed hyperactivity in an auditory network composed of inferior colliculus, medial geniculate, and auditory cortex with side branches to cerebellum, amygdala, and reticular formation. Functional connectivity revealed enhanced coupling within the auditory network and segments of the auditory network and cerebellum, reticular formation, amygdala, and hippocampus. A testable model accounting for distress, arousal, and gating of tinnitus and hyperacusis is proposed.

Loudness perception affected by high doses of salicylate--a behavioral model of hyperacusis.

The major side-effects of high doses of salicylate include sensorial hearing loss and tinnitus. Although salicylate decreases cochlear output, it enhances the evoked potentials recorded from the central auditory system (CAS), suggesting an increase to sound sensitivity. However, the loudness change after salicylate administration has not yet been directly measured. In this study, we established an operant conditioning based behavioral task in rats and measured their loudness perception changes before and after high doses of salicylate injection (250 mg/kg, i.p.). We found that high doses of salicylate induced a significant increase to loudness response in 40% of the rats (out of 20 rats), suggesting a hyperacusis behavior. In another 40% of rats, a rapid increase of loudness response was detected, suggesting loudness recruitment. The reaction time of the rats was also measured during the loudness tests before and after salicylate exposure. The reaction time level functions are highly correlated to the loudness response functions. Our studies confirmed that increased sound sensitivity, which is commonly seen in patients with tinnitus and hyperacusis, can be induced by high doses of salicylate. This loudness change induced by salicylate may be related with hypersensitivity in the CAS.

Amygdala hyperactivity and tonotopic shift after salicylate exposure.

The amygdala, important in forming and storing memories of aversive events, is believed to play a major role in debilitating tinnitus and hyperacusis. To explore this hypothesis, we recorded from the lateral amygdala (LA) and auditory cortex (AC) before and after treating rats with a dose of salicylate that induces tinnitus and hyperacusis-like behavior. Salicylate unexpectedly increased the amplitude of the local field potential (LFP) in the LA making it hyperactive to sounds≥60 dB SPL. Frequency receptive fields (FRFs) of multiunit (MU) clusters in the LA were also dramatically altered by salicylate. Neuronal activity at frequencies below 10 kHz and above 20 kHz was depressed at low intensities, but was greatly enhanced for stimuli between 10 and 20 kHz (frequencies near the pitch of the salicylate-induced tinnitus in the rat). These frequency-dependent changes caused the FRF of many LA neurons to migrate towards 10-20 kHz thereby amplifying activity from this region. To determine if salicylate-induced changes restricted to the LA would remotely affect neural activity in the AC, we used a micropipette to infuse salicylate (20 µl, 2.8 mM) into the amygdala. Local delivery of salicylate to the amygdala significantly increased the amplitude of the LFP recorded in the AC and selectively enhanced the neuronal activity of AC neurons at the mid-frequencies (10-20 kHz), frequencies associated with the tinnitus pitch. Taken together, these results indicate that systemic salicylate treatment can induce hyperactivity and tonotopic shift in the amygdala and infusion of salicylate into the amygdala can profoundly enhance sound-evoked activity in AC, changes likely to increase the perception and emotional salience of tinnitus and loud sounds. This article is part of a Special Issue entitled: Tinnitus Neuroscience.

Gap detection methods for assessing salicylate-induced tinnitus and hyperacusis in rats.

PURPOSE: A variety of options for behavioral assessment of tinnitus in laboratory animals are available to researchers today. These options are briefly reviewed, followed by data suggesting that gap detection procedures might be used to efficiently measure acute, salicylate-induced tinnitus and possibly hyperacusis in rats. METHOD: Fischer Brown Norway rats (n = 10) were given intraperitoneal injections of 350 mg/kg sodium salicylate on 2 consecutive days, and the effects on gap detection were observed across 9 different frequency bands. Pretest, posttest, and washout data were collected. An additional 4 rats were each given 4 different doses of sodium salicylate (0, 150, 250, and 300 mg/kg), and gap detection and prepulse inhibition were measured. RESULTS: Significant gap detection deficits were observed from pre- to posttest that were consistent with tinnitus. Consistent gap detection deficits were found using broadband noise backgrounds, while significant improvements in responding to frequency-specific test bands were found. Similar effects were repeated in the dose response portion of the study. CONCLUSIONS: Gap detection procedures efficiently measured salicylate-induced changes in behavior that were consistent with the presence of tinnitus. In addition, the reliable, stronger responses at many frequencies after salicylate injections suggest the possibility of measuring a hyperacusis-like phenomenon using these methods.

Trimethyltin disrupts loudness recruitment and auditory threshold sensitivity in guinea pigs.

Trimethyltin (TMT) impairs auditory thresholds within minutes of systemic administration. However, there are no data which relate to the output of the auditory nerve at sound levels above threshold. In this experiment, we evaluated the functional effects of TMT on the auditory threshold by identifying the sound level which just produced a detectable compound action potential (CAP). We also assessed outer hair cell function by measuring the cochlear microphonic (CM), a nonpropagated ac potential which is phase-locked to the stimulus. Finally, we measured the growth of the N1 amplitude as a function of stimulus intensity at levels above threshold and of the summating potential (SP), a dc potential which has multiple generators. To isolate cochlear from systemic effects of TMT, the agent was applied directly to the round window, a structure separating the middle and inner ear, of anaesthetized guinea pigs. We show that TMT applied to the round window membrane can disrupt the function of the cochlea. Measurements of auditory function at supra-threshold levels showed clearly that TMT reduced the amplitude of N1 while having no measurable effect on the SP. These findings indicate that TMT blocks the recruitment of neuronal elements by loud sound. This pattern of impairment differs from that observed with aminoglycoside antibiotics, hypothermia, and presbycusis in which loudness recruitment has been reported.

[Dynamics of the recruitment phenomenon in chemical industry workers]. / Dinamika v rekruitman fenomena pri rabotitsi ot khimicheskata promishlenost.

The state of auditory function, the changes in the over-threshold tests for recruitment phenomenon respectively, characteristic for the affection of the sound-receiving links of the auditory analyzer, have dynamically been observed (at interval of 3 to 6 months) among 100 workers from chemical industry. In addition of the otorhinolaryngological examination and acoumetric study of hearing acuity, some tonal threshold and over-threshold audiometric examinations have been performed. A definite correlation has been established between the changes in the hearing function and the length of service of the workers. The data about the over-threshold studies reveal that the tests for recruitment phenomenon become more often positive in the workers, being organic solvents, paints and varnishes. The auditory disorders were observed in the region of high frequencies, being with sound-receiving character. The test of Carhardt became positive rather early, interpreted as early disorder of the processes of adaptation. The approaches of the early diagnostics of hearing disorders are presented as a result from the study.