Tinnitus In Animals Research Articles

Incorporating Auditory Cortex Potentials and Gap Pre-pulse Inhibition of Acoustic Startle: A Probable Way to Objectively Assess Tinnitus

Background and Objectives: Tinnitus is a complex condition that varies in loudness, quality, location, and distress. Different definitions, heterogeneity, and lack of objective measuring have challenged the understanding the mechanisms involved and definitive cure. The integrative model correlates each of these characteristics to separate parallel and overlapping subnetworks that process tinnitus’s perception and emotional reaction. Many of these networks are common with the gap pre-pulse inhibition of acoustic startle (GPIAS) neural circuity. GPIAS, which measures tinnitus in animals, has recently been used for humans with various recording methods. The present study aimed to review the evidence achieved with gap stimuli in patients with tinnitus to support the potential of cortical responses recorded with the GPIAS stimulus and to objectively detect tinnitus in humans. Methods: Studies were identified by searching electronic databases with relevant keywords. Results: The role of the auditory cortex in processing short gaps, the possibility of evaluating the gap detection ability with GPIAS, and the advantage of cortical responses in reflecting both stimulus properties and different aspects of tinnitus emphasize the importance of this issue. The results of most studies have proven the gap detection deficiency in tinnitus. However, the validity of the auditory startle reflex still needs to be verified due to the inherent variability and different methods. Conclusion: Further human studies are recommended because the perception of tinnitus can be controlled. An appealing research line in this area is multi-channel cortical evoked potentials. Defects of GPIAS with cortical recording can indicate tinnitus.

Nitric oxide signalling underlies salicylate-induced increases in neuronal firing in the inferior colliculus: A central mechanism of tinnitus?

The anti-inflammatory drug salicylate induces tinnitus in animals and man. Salicylate reduces cochlear output but causes hyperactivity in higher auditory centres, including the inferior colliculus (the auditory midbrain). Using multi-electrode recording in anaesthetised guinea pigs (Cavia porcellus), we addressed the hypothesis that salicylate-induced hyperactivity in the inferior colliculus involves nitric oxide signalling secondary to increased ascending excitatory input.Systemic salicylate (200 mg/kg i.p., 0 h) markedly increased spontaneous and sound-driven neuronal firing in the inferior colliculus (3-6 h post drug), with both onset and sustained responses to pure tones being massively increased. Reverse microdialysis of increasing concentrations of salicylate directly into the inferior colliculus (100 µM-10 mM, from 0 h) failed to mimic systemic salicylate. In contrast, it caused a small, transient, increase in sound-driven firing (1 h), followed by a larger sustained decrease in both spontaneous and sound-driven firing (2-5 h). When salicylate was given systemically, reverse microdialysis of the neuronal nitric oxide synthase inhibitor L-methyl arginine into the inferior colliculus (500 mM, 2-6 h) completely blocked the salicylate-induced increase in spontaneous and sound-driven neuronal firing.Our data indicate that systemic salicylate induces neuronal hyperactivity in the auditory midbrain via a mechanism outside the inferior colliculus, presumably upstream in the auditory pathway; and that the mechanism is ultimately dependent on nitric oxide signalling within the inferior colliculus.Given that nitric oxide is known to mediate NMDA receptor signalling in the inferior colliculus, we propose that salicylate activates an ascending glutamatergic input to the inferior colliculus and that this is an important mechanism underlying salicylate-induced tinnitus.

Proposal of conditional random inter-stimulus interval method for unconstrained enclosure based GPIAS measurement systems.

Gap prepulse inhibition of acoustic startle (GPIAS) method has been used effectively for the objective assessment of tinnitus in animals. Among two types of enclosures for the GPIAS, the unconstrained type carries less risk of animal death due to the absence of binding stress in the enclosure, and lack of need for alteration to animal size variation as it grows. However, animals' voluntary movements, which have no relation to the startles evoked by acoustic stimuli, are problematic, as they cannot be excluded in the case of the unconstrained enclosure based GPIAS measurement system. In order to discount voluntary movements which are not associated with external acoustic stimuli, we propose the conditional random inter-stimulus interval (CR ISI) method for unconstrained enclosure based GPIAS measurement. With the proposed ISI method, the unconstrained enclosure based acoustic startle response measurement system has been implemented in this paper. As a result, the effectiveness of the proposed CR ISI method has been verified and compared with those of conventional ISI methods through animal experiments using SD-rats. The experimental results showed that abnormal startle responses and invalid GPIAS values caused by motion were prevented when our proposed CR ISI method was applied to our implemented system. It was also verified that our proposed CR ISI method is advantageous in reducing the total experimental time for acquiring normal startle responses and valid GPIAS values, compared to conventional ISI methods, since our proposed CR ISI can begin the acoustic stimulation only when the animal gets stable and motionless.

Gap-induced reductions of evoked potentials in the auditory cortex: A possible objective marker for the presence of tinnitus in animals

Animal models of tinnitus are essential for determining the underlying mechanisms and testing pharmacotherapies. However, there is doubt over the validity of current behavioural methods for detecting tinnitus. Here, we applied a stimulus paradigm widely used in a behavioural test (gap-induced inhibition of the acoustic startle reflex GPIAS) whilst recording from the auditory cortex, and showed neural response changes that mirror those found in the behavioural tests. We implanted guinea pigs (GPs) with electrocorticographic (ECoG) arrays and recorded baseline auditory cortical responses to a startling stimulus. When a gap was inserted in otherwise continuous background noise prior to the startling stimulus, there was a clear reduction in the subsequent evoked response (termed gap-induced reductions in evoked potentials; GIREP), suggestive of a neural analogue of the GPIAS test. We then unilaterally exposed guinea pigs to narrowband noise (left ear; 8–10 kHz; 1 h) at one of two different sound levels – either 105 dB SPL or 120 dB SPL – and recorded the same responses seven-to-ten weeks following the noise exposure. Significant deficits in GIREP were observed for all areas of the auditory cortex (AC) in the 120 dB-exposed GPs, but not in the 105 dB-exposed GPs. These deficits could not simply be accounted for by changes in response amplitudes. Furthermore, in the contralateral (right) caudal AC we observed a significant increase in evoked potential amplitudes across narrowband background frequencies in both 105 dB and 120 dB-exposed GPs. Taken in the context of the large body of literature that has used the behavioural test as a demonstration of the presence of tinnitus, these results are suggestive of objective neural correlates of the presence of noise-induced tinnitus and hyperacusis.

Untangling the effects of tinnitus and hypersensitivity to sound (hyperacusis) in the gap detection test

In recent years, there has been increasing use of the gap detection reflex test to demonstrate induction of tinnitus in animals. Animals with tinnitus show weakened gap detection ability for background noise that matches the pitch of the tinnitus. The usual explanation is that the tinnitus ‘fills in the gap’. It has recently been shown, however, that tinnitus is commonly associated with hyperacusis-like enhancements of the acoustic startle response, a change which might potentially alter responses in the gap detection test. We hypothesized that such enhancements could lead to an apparent reduction of gap suppression, resembling that caused by tinnitus, by altering responses to the startle stimulus or the background noise. To test this hypothesis, we compared gap detection abilities in 3 subsets of noise-exposed animals with those in unexposed controls. The results showed that exposed animals demonstrated altered gap detection abilities, but these alterations were sometimes explained as consequences of hyper-responsiveness to either the startle stimulus or to the background noise. Two of the three subsets of animals studied, however, displayed weakened gap detection abilities that could not be explained by enhanced responses to these stimuli or by reduced sound sensitivity or a reduction of temporal processing speed, consistent with the induction of tinnitus. These results demonstrate that not only hearing loss but also changes in sensitivity to background noise or to startle stimuli are potential confounds that, when present, can underlie changes in gap detection irrespective of tinnitus. We discuss how such confounds can be recognized and how they can be avoided.

Psychophysical and neural correlates of noised-induced tinnitus in animals: Intra- and inter-auditory and non-auditory brain structure studies

Tinnitus, a ringing in the ear or head without an external sound source, is a prevalent health problem. It is often associated with a number of limbic-associated disorders such as anxiety, sleep disturbance, and emotional distress. Thus, to investigate tinnitus, it is important to consider both auditory and non-auditory brain structures. This paper summarizes the psychophysical, immunocytochemical and electrophysiological evidence found in rats or hamsters with behavioral evidence of tinnitus. Behaviorally, we tested for tinnitus using a conditioned suppression/avoidance paradigm, gap detection acoustic reflex behavioral paradigm, and our newly developed conditioned licking suppression paradigm. Our new tinnitus behavioral paradigm requires relatively short baseline training, examines frequency specification of tinnitus perception, and achieves sensitive tinnitus testing at an individual level. To test for tinnitus-related anxiety and cognitive impairment, we used the elevated plus maze and Morris water maze. Our results showed that not all animals with tinnitus demonstrate anxiety and cognitive impairment. Immunocytochemically, we found that animals with tinnitus manifested increased Fos-like immunoreactivity (FLI) in both auditory and non-auditory structures. The manner in which FLI appeared suggests that lower brainstem structures may be involved in acute tinnitus whereas the midbrain and cortex are involved in more chronic tinnitus. Meanwhile, animals with tinnitus also manifested increased FLI in non-auditory brain structures that are involved in autonomic reactions, stress, arousal and attention. Electrophysiologically, we found that rats with tinnitus developed increased spontaneous firing in the auditory cortex (AC) and amygdala (AMG), as well as intra- and inter-AC and AMG neurosynchrony, which demonstrate that tinnitus may be actively produced and maintained by the interactions between the AC and AMG.

Spontaneous behavior in noise and silence: a possible new measure to assess tinnitus in Guinea pigs.

This study describes two experiments that were conducted in search for a behavioral paradigm to test for tinnitus in guinea pigs. Conditioning paradigms are available to determine the presence of tinnitus in animals and are based on the assumption that tinnitus impairs their ability to detect silent intervals in continuous noise. Guinea pigs have not been subjected to these paradigms yet; therefore, we investigated whether guinea pigs could be conditioned in the two-way shuttle-box paradigm to respond to silent intervals in noise. Even though guinea pigs could be trained relatively easy to respond to the presence of a noise interval, training guinea pigs to silent intervals in noise was unsuccessful. Instead, it appeared that they became immobile when the continuous stimulus was suddenly stopped. This was confirmed by the next experiment, in which we subjected guinea pigs to alternating intervals of noise and silence with a random duration between 30 and 120 s. Indeed, guinea pigs were significantly longer immobile during silence compared to during noise. By interpreting immobility as a signature of perceiving silence, we hypothesized that the presence of tinnitus would reduce immobility in silence. Therefore, we unilaterally exposed one group of guinea pigs to an 11-kHz tone of 124 dB sound pressure level for 1 h. A subset of the exposed animals was significantly more active in silence, but also more active in noise, as compared to the control group. The increased mobility during silent intervals might represent tinnitus. However, the increased mobility in noise of this group implies that the observed behavior could have derived from, e.g., an overall increase in activity. Therefore, conducting validation experiments is very important before implementing this method as a new screening tool for tinnitus. Follow-up experiments are discussed to further elucidate the origin of the increased mobility in both silence and noise.

Animal Behavioral Models of Tinnitus

The pathophysiology of tinnitus is poorly understood and treatments are often unsuccessful. A number of animal models have been developed in order to gain a better understanding of tinnitus. A great deal has been learned from these models regarding the electrophysiological and neuroanatomical correlates of tinnitus following exposure to noise or ototoxic drugs. Reliable behavioral data is important for determining whether such electrophysiological or neuroanatomical changes are indeed related to tinnitus. Of the many documented tinnitus animal behavioral paradigms, the acoustic startle reflex had been proposed as a simple method to identify the presence or absence of tinnitus. Several behavioral models based on conditioned response suppression paradigms have also been developed. In addition to determining the presence or absence of tinnitus, some of the behavioral paradigms have provided signs of the onset, frequency, and intensity of tinnitus in animals. Although none of these behavioral models have been proved to be a perfect model, these studies provide useful information on understanding the neural mechanisms underlying tinnitus.

Neural changes accompanying tinnitus following unilateral acoustic trauma in the guinea pig

Animal models of tinnitus allow us to study the relationship between changes in neural activity and the tinnitus percept. Here, guinea pigs were subjected to unilateral noise trauma and tested behaviourally for tinnitus 8 weeks later. By comparing animals with tinnitus with those without, all of which were noise-exposed, we were able to identify changes unique to the tinnitus group. Three physiological markers known to change following noise exposure were examined: spontaneous firing rates (SFRs) and burst firing in the inferior colliculus (IC), evoked auditory brainstem responses (ABRs), and the number of neurons in the cochlear nucleus containing nitric oxide synthase (NOS). We obtained behavioural evidence of tinnitus in 12 of 16 (75%) animals. Both SFRs and incidences of burst firing were elevated in the IC of all noise-exposed animals, but there were no differences between tinnitus and no-tinnitus animals. There were significant decreases in ipsilateral ABR latencies in tinnitus animals, contrary to what might be expected with a small hearing loss. Furthermore, there was an ipsilateral–contralateral asymmetry in NOS staining in the ventral cochlear nucleus (VCN) that was only apparent in tinnitus animals. Tinnitus animals had a significantly greater number of NOS-containing neurons on the noise-exposed side, whereas no-tinnitus animals did not. These data suggest that measuring NOS in the VCN and recording ABRs supplement behavioural methods for confirming tinnitus in animals, and that nitric oxide is involved in plastic neural changes associated with tinnitus.

Parameter Optimization for Applying the Prepulse Gap Paradigm to Humans

Background and ObjectivesTurner and colleagues introduced a new method that can detect tinnitus in animals. The stimulus is composed of a small background noise that is identical to the pitch of the tinnitus and a large pulse noise that can evoke a startle response. In normal rats, the gap decreases the startle reflex. However, in tinnitus rats, the gap does not decrease the startle reflex. The goal of this study was to optimize the stimulation paradigm so that the prepulse inhibition of N1-P2 amplitude would be maximized in the normal human subjects.Subjects and MethodsSeven normal control subjects without tinnitus were recruited. The stimulus was composed of two different sounds: the softer background noise and the louder pulse noise. A 50 msec silent gap was inserted before the pulse noise as the gap condition (G condition) but not in the no-gap condition (N condition). The averaged amplitude of the N1-P2 cortical response was recorded for the G and N conditions.ResultsThe G/N ratio was the smallest when the gap was 20 msec prior to the pulse noise. The G/N ratio was 84.8±16.8% with the Hanning window and 78.5±5.9% without the window. The G/N ratio was 91.1±24.9%, 78.0±5.4%, and 79.0±18.1% when the intensity of the background noise was 10, 20, and 32 dB SL, respectively. When the intensity of the background noise was 20 and 32 dB SL, the N1-P2 amplitude of the G condition was significantly smaller than that of the N condition.ConclusionsThe optimal stimulus should be composed of the 1 kHz pulse noise without Hanning window. The intensity of the background noise should be 20 dB HL and the location of the gap should be 20 msec prior to the pulse noise. It seems that with these optimized parameters we could expect a 78.0% inhibition of N1-P2 amplitude in normal subjects without tinnitus.

Altered Neuronal Intrinsic Properties and Reduced Synaptic Transmission of the Rat's Medial Geniculate Body in Salicylate-Induced Tinnitus

Sodium salicylate (NaSal), an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB), an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg) showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. NaSal (1.4 mM) decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus.

The gap-startle paradigm for tinnitus screening in animal models: Limitations and optimization

In 2006, Turner and colleagues (Behav. Neurosci., 120:188–195) introduced the gap-startle paradigm as a high-throughput method for tinnitus screening in rats. Under this paradigm, gap detection ability was assessed by determining the level of inhibition of the acoustic startle reflex produced by a short silent gap inserted in an otherwise continuous background sound prior to a loud startling stimulus. Animals with tinnitus were expected to show impaired gap detection ability (i.e., lack of inhibition of the acoustic startle reflex) if the background sound containing the gap was qualitatively similar to the tinnitus pitch. Thus, for the gap-startle paradigm to be a valid tool to screen for tinnitus, a robust startle response from which to inhibit must be present. Because recent studies have demonstrated that the acoustic startle reflex could be dramatically reduced following noise exposure, we endeavored to 1) modify the gap-startle paradigm to be more resilient in the presence of hearing loss, and 2) evaluate whether a reduction in startle reactivity could confound the interpretation of gap prepulse inhibition and lead to errors in screening for tinnitus. In the first experiment, the traditional broadband noise (BBN) startle stimulus was replaced by a bandpass noise in which the sound energy was concentrated in the lower frequencies (5–10 kHz) in order to maintain audibility of the startle stimulus after unilateral high-frequency noise exposure (16 kHz). However, rats still showed a 57% reduction in startle amplitude to the bandpass noise post-noise exposure. A follow-up experiment on a separate group of rats with transiently-induced conductive hearing loss revealed that startle reactivity was better preserved when the BBN startle stimulus was replaced by a rapid airpuff to the back of the rat’s neck. Furthermore, it was found that transient unilateral conductive hearing loss, which was not likely to induce tinnitus, caused an impairment in gap prepulse inhibition as assessed with the traditional BBN gap-startle paradigm, resulting in a false-positive screening for tinnitus. Thus, the present study identifies significant caveats of the traditional gap-startle paradigm, and describes experimental parameters using an airpuff startle stimulus which may help to limit the negative consequences of reduced startle reactivity following noise exposure, thereby allowing researchers to better screen for tinnitus in animals with hearing loss.

Auditory brainstem response as a possible objective indicator for salicylate-induced tinnitus in rats

The auditory response to an acoustic stimulus will usually be suppressed, or masked, by a preceding sound. Here, we show that forward acoustic masking at a high frequency can boost the auditory brainstem response (ABR) in rats injected with a high dose of sodium salicylate (NaSal), a tinnitus inducer. The forward narrow band noise caused a decrease in the amplitude of the ABR to a probe tone burst in normal rats, but caused an unexpected increase in the amplitude at 16 kHz in rats treated with NaSal (300 mg/kg). The observed effect could be manifested in normal rats presented with a background tone added to the masker and the probe, suggesting an underlying mechanism associated with tinnitus. We hypothesize that in NaSal-treated rats, tinnitus can "internally" mask the ABR in a similar way as an external background sound does and the "unmasking" effect of forward masking can result in a rebound of the otherwise suppressed ABR. Our study raises the possibility of using the ABR as an objective indicator for NaSal-induced tinnitus in animals. This article is part of a Special Issue entitled: Tinnitus Neuroscience.

Effects of the potassium ion channel modulators BMS-204352 Maxipost and its R-enantiomer on salicylate-induced tinnitus in rats

Currently, there are no effective pharmacological therapies for chronic tinnitus despite a number of efforts from clinical studies and more recently, studies in animals using compounds to enhance endogenous inhibition or reduce central hyperactivity. The purpose of the current study was to evaluate the therapeutic efficacy of a novel anxiolytic with potassium channel activity in suppressing salicylate induced tinnitus in animals. Kv7 potassium channels are present in the peripheral and central auditory system where they are believed to modulate neural activity. Maxipost, a compound which attenuates hyperexcitability via positive modulation of Kv7.2–Kv7.5 channels, was administered to rats with behavioral evidence of salicylate induced tinnitus. Tinnitus was measured using our previously established animal model, Schedule Induced Polydipsia Avoidance Conditioning, a paradigm where rats were conditioned to drink only during quiet and suppress drinking in the presence of sound. Salicylate alone significantly suppressed licks in quiet but had no effect on licks in sound; results consistent with the presence of tinnitus. Maxipost at 10mg/kg suppressed behavioral evidence of tinnitus as it completely reversed salicylate's suppression of licks in quiet. Unexpectedly, the R-enantiomer of Maxipost, R-Maxipost, which has no anxiolytic effects and negatively modulates Kv7.2–Kv7.5, also suppressed behavioral evidence of tinnitus. Our original hypothesis was that Kv7.2–Kv7.5 channels might play a key role in tinnitus generation and that Maxipost but not R-Maxipost would suppress tinnitus; however, it appears that a shared mechanism between Maxipost and R-xMaxipost, such as inhibition of Kv7.1 channels or activation of BK channels or some novel mechanism common to both compounds, underlies salicylate induced tinnitus as both compounds completely abolished behavioral evidence of tinnitus in a dose-dependent manner. Further studies with specific BK channel agonists/antagonists are necessary to determine the contribution of these channels to other forms of tinnitus or determine novel targets that could be related to tinnitus.

A two-choice sound localization procedure for detecting lateralized tinnitus in animals

Rats were trained in a two-choice procedure to respond in the direction of left and right sounds. Silent trials, on which no sound was presented and for which the animals received no feedback, were interspersed among the sound trials to determine each animal's natural side preference. Following training, the rats were exposed to a loud tone in the ear opposite their side preference. A shift in responding on the silent trials to the side of the exposed ear indicated that the animals were hearing a sound in that ear (i.e., tinnitus). Simulating lateralized tinnitus by presenting a low-level, continuous sound on one side also caused the rats to shift their responding on the silent trials to that side. Sham exposures indicated that halothane/nitrous oxide anesthesia could reinstate tinnitus in animals that had previously tested positive for it. Exposing rats to loud tones of various frequencies indicated that frequencies near the limits of the rat's hearing range were less likely to cause tinnitus than tones in the midrange.

Effects of salicylate application on the spontaneous activity in brain slices of the mouse cochlear nucleus, medial geniculate body and primary auditory cortex

Salicylate is a well-known substance to produce reversible tinnitus in animals and humans as well. It has been shown that systemic application of salicylate changes the neuronal spontaneous activity in several parts of the auditory pathway. The effects observed in central auditory structures in vivo could be based upon the changed afferent cochlear input to the central auditory system or in addition by a direct action of salicylate onto neurons within the auditory pathway. A direct influence of local salicylate application on spontaneous activity of central auditory neurons has already been described for the inferior colliculus (IC) in brain slice preparations. As spontaneous activity within all key structures of the central auditory pathway could play an important role in tinnitus generation, the present study investigated direct effects of salicylate superfusion on the spontaneous activity of the deafferented cochlear nucleus (CN), medial geniculate body (MGB), and auditory cortex (AC) in brain slices. Out of 72 neurons, 73.4% responded statistically significantly to the superfusate by changing their firing rates. 48.4% of them increased and 51.6% decreased their firing rates, respectively. The mean change of firing rate upon salicylate superfusion was 24.4%. All responses were not significantly different between the brain areas. The amount of neurons which responded to salicylate and the mean change of firing rate was much higher in the IC than in the CN, MGB and AC. This contributes to the hypothesis that salicylate-induced tinnitus is a phantom auditory perception mainly related to hyperexcitability of IC neurons. However, the present results suggest that the individual, specific salicylate sensitivity of CN, MGB and AC neurons can modulate the salicylate-induced generation of tinnitus.

M‐Chlorophenylpiperazine exacerbates perception of salicylate‐induced tinnitus in rats

The serotonin receptor 5-HT2c agonist m-chlorophenylpiperazine (mCPP) has been widely used to induce anxiety-like states in animals and anxiety in humans. We here addressed the effect of an intraperitoneal injection of mCPP on the perception of tinnitus in a behavioural protocol based on an active avoidance paradigm. In control saline-treated animals, mCPP did not change compound action potential audiograms or measurable tinnitus. In contrast, mCPP to animals demonstrating salicylate-induced tinnitus exacerbated tinnitus perception by nearly twofold. We went on to test whether manipulation of the peripheral generator of tinnitus (i.e. the cochlea) could extinguish this exacerbated perception by applying the N-methyl-d-aspartate (NMDA) antagonist 7-chlorokynurenate (7-CK) into cochlear fluids using a 7-CK-soaked Gelfoam ball placed on the round window of each of the animals' two ears. In addition to blocking the tinnitus induced by salicylate alone, 50 microm of 7-CK clearly abolished tinnitus in animals receiving salicylate and an injection of mCPP. The demonstration that cochlear NMDA receptor blockade abolishes the exacerbated perception of tinnitus is highly relevant in terms of treatment. In addition to psychotherapeutic treatment that may help to attenuate an individual's perception of tinnitus, targeting cochlear NMDA receptors represents a promising therapeutic strategy, even in depressed or chronically anxious patients.

Tinnitus in hamsters following exposure to intense sound

Hamsters were trained with a conditioned suppression/avoidance procedure to drink in the presence of a broadband noise and/or a tone and to stop drinking in the absence of sound. A variety of tones and loudspeaker locations were used during training so that the animals would respond to a sound regardless of its frequency or location. Four groups of animals then had their left ears exposed to a 10-kHz tone at 124 or 127 dB for 0.5, 1, 2 or 4 h. They were then tested for tinnitus by comparing their performance with that of unexposed animals to determine if they behaved as if they perceived a sound when no external sound was present. The groups exposed for 2 and 4 h tested positive for tinnitus whereas those exposed for 0.5 and 1 h did not. The degree of hearing loss produced by the tone exposure was assessed using behavioral and auditory brainstem response (ABR) procedures. A partial dissociation was found between the hearing loss, as estimated by the ABR, and the results of the tinnitus test in that animals exposed for 1 h had the same hearing loss as the 2- and 4-h exposed animals, but did not test positive for tinnitus. This suggests that the positive scores on the tinnitus test were not due to hearing loss. These results are discussed along with those of previous behavioral studies of tinnitus in animals.

Neurophysiologic Mechanisms of Tinnitus

Research over the past decade has provided new insights into the neural mechanisms likely to produce the false percepts of sound associated with tinnitus. These insights have emerged mainly as a result of electrophysiologic studies, examining changes in brain activity, and behavioral studies, examining changes in perception, in animals that have been treated with well-known tinnitus inducers such as salicylates, quinine, and intense sound. The available evidence, based on electrophysiologic studies, suggests that tinnitus is associated with disturbances in spontaneous neural activity in the auditory system. These abnormalities include increases in spontaneous activity (hyperactivity), changes in the timing of neural discharges (i.e., the temporal firing properties of neurons), and an increase in bursting activity of neurons. Parallel studies using behavioral testing methods have demonstrated that agents, which produce these neural changes, also cause tinnitus in animals. This article reviews the literature concerned with both behavioral evidence for tinnitus in animal models and the associated changes that occur at peripheral and central levels of the auditory system.