Учебники / Auditory Trauma, Protection, and Repair Fay 2008

estimated locus of the exposure-tone frequency. The mean increase in spontaneous rate was paralleled by the increase in the mean neural threshold shift. Similar findings were reported in rats after a unilateral exposure to acoustic trauma, although the increase in spontaneous rate at the 10 kHz locus of the DCN topographic map was not as profound as in the hamster (Zhang and Kaltenbach 1998). The source of the elevated spontaneous rate was not immediately evident, as there was no correspondence between the widths or magnitude of the cochlear lesions and the widths of the DCN topographic map with elevated spontaneous activity.

The same group determined onset latency of the elevated spontaneous activity and the relationship to threshold elevations (Kaltenbach et al. 2000). A nonlinear fluctuation in MSA was found, initially decreasing and then increasing over time. These results could be interpreted as reflecting an initial hearing loss, followed by the delayed emergence of tinnitus. Hamsters were exposed to a 10-kHz tone at 127 dB SPL for 4 h. The MSA of exposed subjects 2 days after acoustic exposure was less than 14 counts per second (CPS); across the mediolateral DCN axis, compared to 34 CPS in control subjects. However, 30 days after exposure the MSA had increased to 78 CPS for the exposed group. It was notable that the mean multiunit threshold shift 2 days after exposure exceeded the threshold shifts at 30 days, suggesting that the observed MSA increase at 30 days was not simply reflecting hearing loss.

Several studies have examined the possible contribution of different patterns and magnitudes of hair cell damage to the reorganization of the DCN topographic map. Cisplatin, a chemotherapeutic agent, is ototoxic and commonly produces hearing loss and tinnitus in humans. Cisplatin predominantly degrades the cochlear outer hair cell system; the attendant tinnitus may arise because of imbalanced neural activity in the type 1 afferents innervating the intact inner hair cells and the type 2 afferents innervating damaged outer hair cells. Hamsters were evaluated for changes in MSA surface recordings from the DCN after a range of systemic cisplatin doses that produced hair cell damage (Kaltenbach et al. 2002). Although the level of cochlear damage did not correspond to cisplatin dose, in general the inner hair cell loss was limited to less than 1% in the basal turn of the cochlea, while a greater level of outer hair cell loss was evident in the apical and basal turns of the cochlea. Subjects with only mild cochlear lesions did not exhibit a significant increase in DCN MSA. However, subjects with selective outer hair cell lesions in the basal turn did show evidence of increased activity. Intermediate and severe outer hair cell loss in the basal half of the cochlea, without associated inner hair cell lesions, correlated with increased activity in the high-frequency region of the DCN (r = 0.89). However, extensive outer hair cell damage with associated inner hair cell damage was not as strongly correlated (r = 0.51) with MSA. Kaltenbach concluded that outer hair cell damage was an important factor in the development of increased spontaneous activity in the DCN after cisplatin ototoxicity.

Caution should be used in interpreting the previously cited DCN–spontaneous activity research: Although elevated DCN neural activity appears to be reliably

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produced by various types of acoustic trauma, conditions commonly associated with tinnitus in humans, tinnitus itself was not measured in the animal subjects of these studies. Caution should also be exercised in interpreting the observed changes in multiunit activity. DCN surface recordings of multiunit activity do not discriminate neural type or the direction of activity in the auditory pathway. Some of these issues were experimentally addressed in a study reporting elevated single-unit spontaneous activity in DCN fusiform cells of chinchillas with psychophysical evidence of tinnitus (Brozoski et al. 2002). Fusiform neurons are responsible for the major rostral output of the DCN. Tinnitus was measured in the chinchillas 18 months after a unilateral exposure to a 4 kHz tone at 80 dB SPL. All of the animals were behaviorally trained and psychophysically tested (see Table 4.1). Exposed subjects displayed evidence of tinnitus that was tonal and centered at 1 kHz. Both spontaneous activity and stimulus-driven activity at a frequency identical to the psychophysical tinnitus frequency were significantly elevated. Auditory brain stem response thresholds were minimally elevated at the tinnitus frequency, indicating that the DCN changes were not reflecting hearing loss.

The role of the DCN in either the development or the persistence of tinnitus is still in question. Kaltenbach proposed a neural circuit in which type II fiber deafferentation from selective outer hair cell damage resulted in decreased input to granule cells. Loss of input to these excitatory neurons would decrease synaptic drive on inhibitory interneurons such as cartwheel cells and stellate cells, with resulting loss of inhibition at the level of the fusiform cells (Kaltenbach 2006; Kaltenbach et al. 2005). Bauer proposed an alternate route of tinnitus development. The selective loss of high spontaneous rate (SR), large-diameter primary afferent fibers (ANF) will selectively reduce the input to small cells within the deep DCN. Small cells are physiologically characterized by type II responses, which include low spontaneous activity and high thresholds, and morphologically include a mixture of cell types, including interneurons and vertical cells (Young and Voigt 1982). Type II units provide inhibitory input to type IV units, the DCN principal cells. If, following acoustic trauma, a major source of inhibition of the fusiform cells is lost via the pathway of high-SR-ANF to the vertical cells of the deep DCN, the elevated SR of fusiform cells is predicted. Elevated DCN fusiform output could serve either as a trigger for tinnitus-related neural activity rostral to the cochlear nucleus, or as a generator of the chronic neural signal for tinnitus.

The role of DCN fusiform cells as the sole source of chronic tinnitus was not supported by recent work showing persistent psychophysical evidence of tinnitus in rats after DCN ablation (Brozoski and Bauer 2005). Rats were behaviorally trained and tested for acoustic-trauma-induced tinnitus. After the tinnitus was psychoacoustically characterized, both experimental and control subjects had unilateral and bilateral DCN ablations, and then were retested for tinnitus. Bilateral dorsal DCN ablation did not significantly affect the psychophysical evidence of tinnitus and ipsilateral DCN ablation increased the evidence of tinnitus compared to pre-ablation performance. These results suggest that the DCN does not act as a simple feed-forward source of chronic tinnitus.

Nevertheless, it is possible that initial DCN hyperactivity after cochlear trauma triggers persistent pathological neuroplastic changes distributed across more than one level of the auditory system. The DCN may also contribute to the chronic pathology of tinnitus, albeit not exclusively, since tinnitus was enhanced by ipsilateral DCN ablations. The ipsilateral ablation data suggest that asymmetric input from the DCN to higher centers may also be an important factor in tinnitus pathophysiology.

4.4 Inferior Colliculus

The inferior colliculus (IC) has been suggested as a possible tinnitus generator. Known alterations in glutamic acid decarboxylase (GAD), glutamate neurotransmitters, and neural coding occur under conditions of decreased or abnormal auditory input such as aging, salicylate toxicity, and acoustic trauma (Willott and Lu 1981; Jastreboff and Sasaki 1986; Salvi et al. 1990; Caspary et al. 1995). Very few studies have directly implicated the IC with neurophysiological correlates of the behavioral evidence of tinnitus.

Jastreboff and Brennan’s work established that salicylate treatment could produce tinnitus in rats (Jastreboff et al. 1988a,b). Subsequent work has examined salicylate-induced effects along the auditory pathway. Increased c-fos expression was noted in rat IC but not in cochlear nucleus, after moderate salicylate exposure (Wu et al. 2003). The c-fos staining was most prominent in the 9- to 10kHz region of the IC, corresponding to the reported frequency of tinnitus in psychophysical testing (Bauer et al. 1999) and the frequency of increased spontaneous activity in electrophysiologic studies (Chen and Jastreboff 1995; Wang et al. 2002).

4.5 Auditory Cortex

Because tinnitus is a conscious perception, that is, one must be aware of it for tinnitus to exist, the auditory cortex (AC) is a logical site for investigation of potential neurophysiological correlates. Several hypotheses about the role of the AC in tinnitus have been offered: They include increased spontaneous activity and changes in the temporal pattern of neural activity, such as bursting, and alterations of tonotopic representation that lead to enhanced synchrony. A number of animal studies have demonstrated altered neural activity and processing within the primary and secondary AC after auditory damage similar to that causing tinnitus in humans. However, these studies of cortical neurophysiology have not directly measured tinnitus in their animal subjects.

Salicylate has been shown to increase burst-firing in secondary AC (AII) neurons, but not in primary AC (AI) (Ochi and Eggermont 1996). This is consistent with the observation that salicylate produced bursting in the external nucleus of the IC, a region with significant input to AII. However, the salicylate results are not consistent with the central effects of other types of cochlear insult, suggesting that the pathophysiology of salicylate-induced and trauma-induced tinnitus might be

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quitedifferent.Thesignificanceofneuralburstingforchronictinnitus,asopposedto acute tinnitus, and salicylate-induced tinnitus, is not certain. For example, immediately after acoustic trauma, Norena and Eggermont (2003) reported AI activity in cats that did not parallel salicylate effects: Synchronized firing was evident in neurons with characteristic frequencies CFs one and two octaves above the trauma frequency, and bursting was not specific to any frequency region. More importantly, hours after trauma, bursting was no longer evident but neural synchrony increased in frequency regions both below and one to two octaves above the trauma frequency. Elevated spontaneous activity was also reported, but it was restricted to frequency bands above and below the trauma frequency, a finding that contrasts with the immediate effects of acoustic trauma on spontaneous activity in subcortical structures such as the CN and IC (Salvi et al. 1978; Wang et al. 1996; Kaltenbach et al. 2000).

The inconsistencies between salicylate-induced and trauma-induced tinnitus may be real, particularly in light of the likely difference between the peripheral effects of each treatment: Salicylate ototoxicity produces a short-term increase in cochlear output via the auditory nerve; in contrast, auditory trauma generally produces a long-term decrease in cochlear output and a partial de-afferentation. The perception of tinnitus may be similar in each instance, but the pathophysiology may be quite different. Inconsistencies between the cortical effects and subcortical effects of auditory trauma, on the other hand, may be more apparent than real. Following trauma, the frequency locus of effect, and the time course of the effects, may differ at each level of the auditory system. The pathophysiology of chronic tinnitus produced by auditory trauma may reflect a cascade of events, beginning with cochlear damage, unfolding with neuroplastic alterations at each level in the central auditory system, and concluding with changes in cortical processing.

Advances in imaging technology, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), have enabled the study of ongoing neural activity in awake humans under normal and pathologic conditions, including tinnitus. Whether the imaged regions of abnormal activity are in fact serving a causal role in the perception of tinnitus is not yet clear. Several imaging studies of human tinnitus have identified auditory cortex as a potentially critical site. It remains to be established whether the identified regions are active because of an intrinsic pathological process or if they have been indirectly activated by a primary generator located elsewhere.

The recently developed diagnostic and treatment technique of transcranial magnetic stimulation (TMS) has opened a novel avenue for investigating the causal and associational aspects of tinnitus-related cortical activity. In TMS, a brief intense magnetic field is applied to the scalp. The magnetic pulse induces a temporary focal disruption of neural activity in a discrete area of adjacent cortex. This “virtual lesion” briefly, and reversibly, disrupts cortical activity and allows the investigator to determine if the cortical region of interest contributes to a specific behavior or perception. This technique may be useful for investigating cortical mechanisms of tinnitus and may also be of clinical value as a treatment for some forms of tinnitus.

5. Treatment Principles

Development of targeted effective therapies for chronic tinnitus has been hampered by poor understanding of tinnitus pathophysiology and limited hypotheses about mechanisms. Consequently, many clinical trials have been derived from anecdotal reports of tinnitus treatment successes, or adopted from other clinical indications such as pain, epilepsy, and depression. Not surprisingly, such blind empiricism has had limited success. The excellent review of randomized placebo-controlled trials by Dobie is recommended for anyone interested in therapeutic interventions (pharmacologic, surgical, electrical, and behavioral) for tinnitus (Dobie 1999).

There are many challenges inherent in studying a complex phenomenon such as tinnitus in humans. The impact of genetic diversity and the timing and extent of cochlear damage that occurs over a lifetime are two factors that are outside experimental control. Although theoretically amenable to experimental control, the powerful placebo effect that accompanies any intervention for a subjective condition must be addressed with particular care and skill. Finally, the dichotomy between the perception of tinnitus and the associated reactive response to tinnitus (anxiety, depression, impaired concentration, sleep disruption) lends an additional complexity to unraveling mechanisms that are responsible for tinnitus. Clinical studies must address these complex features to accurately determine effective treatments for specific patient populations and types of tinnitus.

Principle-driven tinnitus treatments, based on likely mechanisms, include pharmacologic interventions directed at enhancing inhibitory neurotransmitter function (loss of inhibition), acoustic modulation of the auditory pathway using sound stimulation (peripheral deafferentation), electrical stimulation of the auditory pathway, and magnetic stimulation of auditory cortex (deafferentation and abnormal pattern of neural activity). Clinical research evaluating these treatments is either preliminary or has not yet been implemented in placebo-controlled trials.

5.1 Pharmacologic Interventions for Tinnitus

Pharmacologic interventions for tinnitus, derived from experimentally determined mechanisms, are few. Several independent lines of laboratory research have suggested that tinnitus arises from a loss of inhibition within the auditory pathway. A likely target for therapeutic intervention is the neurotransmitter-aminobutyric acid (GABA). Basic research indicates GABA is a widely distributed, almost exclusively inhibitory, neurotransmitter; the functional role of GABA in central auditory processing has been described in some detail (Caspary et al. 1987, 1994); laboratory studies investigating acute or slow, progressive deafferentation caused by cochlear damage, have identified alterations in GABA at several levels in the auditory pathway (Eggermont 2005).

In a well-controlled trial, alprazolam effectively reduced the subjective loudness of chronic tinnitus (Johnson et al. 1993). Alprazolam is a

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benzodiazepine and the site of action is the GABA receptor. Gabapentin, a GABA analogue, reduced the perceptual loudness and annoyance of chronic tinnitus in a dose-dependent manner, as established in a placebo-controlled study (Bauer and Brozoski 2006). The drug was most effective for a clinical subpopulation whose tinnitus was associated with acoustic trauma, and was less effective for a subpopulation without evidence of acoustic trauma. The effect was dose dependent and reversible with discontinuation of the active medication. It is also notable that a test of gabapentin using an animal model, showed that it significantly decreased, but did not eliminate, psychophysical evidence of tinnitus (Bauer and Brozoski 2001).

5.2 Reorganization of Auditory Cortex Through Sound

Stimulation

Norena and Eggermont (2003) demonstrated the cortical reorgani-zation that occurs in cat after acoustic trauma. The reorganization was presumed to occur as a result of peripheral deafferentation leading to altered tonotopic representation of critical frequency bands within AI and AII. Cats with trauma-induced cortical reorganization were subsequently exposed to chronic acoustic stimulation with either low-frequency or high-frequency broad-band sound. Only the cats that were stimulated with high-frequency sound displayed a normalization of the cortical tonotopic reorganization (Norena and Eggermont 2003). These results suggest that pathology resulting from deafferentation can be modulated by acoustic stimulation.

Sound stimulation using various delivery techniques is currently in clinical use for the treatment of tinnitus. While derived from an experimentally determined mechanism, data on the efficacy of sound-stimulation therapy for reducing the loudness and annoyance of tinnitus is mixed. Flor used a protocol of daily auditory discrimination training that was tailored to the specific tonality of the individual’s tinnitus (Flor et al. 2004). The most benefit was obtained by subjects who used daily regular training. Hiller (Hiller and Haerkotter 2005) examined the effect of sound stimulation provided by a white noise generator combined with cognitive therapy directed at reducing the reactive components of disturbing tinnitus. The addition of sound stimulation did not enhance the improvement that occurred with cognitive therapy alone.

5.3 Reorganization of Auditory Cortex Through Electric

and Magnetic Stimulation

Several studies have investigated the effect of cortical stimulation on the perception and annoyance of chronic tinnitus. Plewnia et al. (2003) transiently suppressed the perception of chronic tinnitus in a group of subjects by applying TMS to secondary auditory cortex. Kleinjung et al. (2005a, b) used PET and MRI to identify regions of increased activity in auditory cortex associated with chronic

severe tinnitus. Neuronavigational techniques were employed to target these areas for repetitive TMS. In a placebo-controlled crossover design, improvement in tinnitus annoyance occurred in the actively treated group but not in the sham treated group. Improvement in tinnitus severity occurred in 11 of 14 subjects within 1 to 6 days after treatment. However, at 6 months follow-up tinnitus was improved in 8 of 14 and had worsened from baseline in the remaining 6 subjects.

Using TMS, DeRidder et al. (2006) identified subjects for implantation of stimulating electrodes in AI and AII. Interestingly, implanted subjects with unilateral tonal tinnitus experienced the largest reduction in tinnitus loudness (97%) compared to 24% reduction in subjects with tinnitus characterized as white noise. Important caveats were that the tinnitus had to be responsive to TMS and be of recent onset. Inclusion of a placebo control would have strengthened the conclusions, as subjects responsive to TMS may be particularly strong placebo responders and therefore biased toward a positive response after electrode implantation. It is also known that for many people new onset tinnitus gradually improves over time through presumably a normal habituation process. The positive results observed by De Ridder, et al., although highly intriguing, are potentially confounded by the phenomenon of spontaneous recovery.

6. Summary

Chronic tinnitus is a complex phenomenon that affects millions of people and poses a significant challenge to both the scientific community and clinical practice. Until the pathophysiology of this heterogeneous disorder is understood in greater detail, effective treatments will remain elusive. The use of existing animal models, and the development of new ones, will play an important role in future research directed at understanding the mechanisms responsible for tinnitus. Current challenges that can be addressed by appropriate animal models include identification of the site(s) in the auditory, and perhaps nonauditory, pathway that are involved in generating the phantom perception. Several regions have been linked to the tinnitus signal, such as the DCN, the IC, and auditory cortex. Much work needs to be done to determine if these sites are critical triggers or generators of tinnitus and the neural mechanisms that result in tinnitus.

The development of new treatments derived from experimental principles is exciting and holds great potential for the millions of people who suffer from tinnitus. Targeted pharmacotherapy, based on plausible mechanisms, and related to specific etiologies, needs to be further developed. Rigorously conducted, wellcontrolled clinical studies will serve a critical role as emerging technologies, such as magnetic transcranial stimulation and direct brain stimulation, are applied to the treatment of tinnitus. Chronic tinnitus will yield to effective treatment as both the basic and applied research progresses.

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Acknowledgments. The research of the authors in the areas of animal psychophysics, cochlear anatomy and brainstem electrophysiology was sponsored by the National Institutes of Health RO1 NIDCD RO1 DC04830. The clinical research investigating gabapentin was sponsored by the Tinnitus Research Consortium.

Addendum: Animal Models of Tinnitus

A.1 Primer of Conditioning Principles

The principles on which all of the animal models of tinnitus rely are derived from conditioning paradigms in experimental psychology. This large, well-codified body of knowledge describes the fundamental principles of conditioning and learning in many species. Perhaps the most fundamental principle of instrumental, or operant, conditioning, is the law of effect, which states that behavior is modified by its consequences. More specifically, a positively reinforcing stimulus (Sr+) such as water for a water-deprived subject or food for a nutrient-deprived subject, when contingent on an emitted behavior (such as licking a spout, pressing a lever, or moving to a specific location), will increase, or maintain, the frequency of the behavior. Similarly, a punishing, or aversive, stimulus (Sr–), such as an applied electric current, when contingent on an emitted behavior, will decrease the frequency of that behavior. Behavior can also be modified by informative or discriminative stimuli (Sd). Discriminative stimuli are contextual, typically continuously present, and inform the subject of stimulus contingencies, e.g., the likelihood of an Sr+ or Sr–, if an appropriate response is emitted. An Sd signaling a contingent Sr+ is called a positive discriminative stimulus (often, S+), and an Sd signaling a contingent Sr–is a negative discriminative stimulus (often, S–). A rat can be trained (conditioned) to press a lever for food (Sr+) when audible sound (S+) is present. In addition, the rat can be conditioned to stop lever pressing in the absence of sound (S–) if a mild electric foot shock (Sr–) is made contingent on lever pressing. Because S+ and S– differentially affect behavior, testing animals with Sd’s of different values enables an experimenter to objectively quantify what the animal hears. Finally, extinction refers to a procedure of removing contingent stimuli, either Sr+ or Sr–, or both. Extinction permits an experimenter to measure behavior without immediate contingencies, in which case the influence of previous contingencies may be assessed.

A.2 The Jastreboff–Brennan Model

Jastreboff and Brennan established that salicylate-induced tinnitus could be objectively measured in rats, by applying the previously described conditioning principles (Jastreboff et al. 1988a, b). Using a conditioned-suppression psychophysical method (Smith 1970), Jastreboff and Brennan trained waterdeprived rats to lick from a spout to obtain their daily water ration. Licking is a

natural behavior for a rodent, and does not require lengthy training. A free-field auditory stimulus (the S+) was present in the test chamber when water was available (Sr+). The same stimulus was also continually presence in the rats’ home cage, as well as in the experimental chamber. The S– was offset of the background sound, which signaled the contingency of a mild footshock (Sr–). In the conditioned suppression paradigm the rat can avoid the Sr– by not making contact with the water spout during S–. Suppression of licking indicates the rat’s detection of S–. Typically, suppression is quantified by a relative measure expressed as the ratio of lick rate during S– (B) compared to the behavior during S+ (A). The suppression ratio, R = B/A + B, is a standard metric for quantifying behavior in this paradigm and can be used to quantify the effect of S–. When the conditioned suppression paradigm is applied to stimulus-controlled behavior, R provides a running index of the subject’s detection and interpretation of S–.

It is important to note that the Jastreboff–Brennan experiments used the conditioned suppression method to quantify salicylate-induced tinnitus by determining R during extinction of the conditioned suppression. Extinction was used so that the experimenters could assess the rats’ interpretation of S– as affected by immediately prior conditions. For this purpose subjects were divided into three groups: controls, which did not receive salicylate; an SA group, which received Na-salicylate only after suppression training (Sr− removed); an SB group, that received Na-salicylate during and after suppression training (Sr−contingent, then removed). All subjects were water deprived and trained to lick from a spout with a background of audible noise (Sr+). Suppression training was identical for all groups, the Sr− being foot shock, delivered at the end of the S– presentation. The objective of the Na-salicylate treatments was to induce acute salicylate-induced tinnitus either during training (SB group), where it would be associated with the S– Sr− suppression contingency, or after training (SA group), where it would not be associated with the S– Sr− suppression contingency.

Different suppression ratios were obtained for each of the three groups during extinction: the SA group had the highest R (little suppression), the SB group had the lowest R (deep suppression), and the control group had an intermediate value of R. The following interpretation was given: All groups have the same S+, but not the same functional S–, which was determined by their suppression training. For all groups the nominal S– in extinction was sound off, as it was in training. However, functionally the S– in extinction was different for each group. SA subjects had the highest extinction R because with Na-salicylate on board they were incapable of hearing silence, their functional S–. In contrast, SB subjects had salicylate-induced tinnitus all along, and when tested in extinction, SB subjects suppressed deeply (low R) because tinnitus was their training S–. Finally, control extinction was intermediate between the SA and the SB groups because for the control group the S– was both functionally and nominally the same (no sound) during training and extinction testing.

The Jastreboff et al. (1988a, b) experiment was the first to demonstrate the perceptual consequences of salicylate ototoxicity in animals. They established that animals could experience tinnitus and that the effects of tinnitus could be

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objectively quantified. Nevertheless, a substantial limitation of their model was the reliance on the extinction test. This necessarily restricts the time frame in which an animal with tinnitus can be studied. Extinction is a transition state which is complete after four to five experimental sessions, at which point all differences between treatment groups disappear. This limits opportunities for manipulating tinnitus or studying changes that occur over time, such as the effects of aging on tinnitus. To a lesser extent, the Jastreboff–Brennan model is also hampered by reliance on licking behavior as the dependent measure. Licking in the rodent is episodic as it is in most mammals, thereby providing a baseline with considerable variability. Although correction methods exist for high variability baselines, corrections add a layer of complexity and potentially introduce additional artifacts.

A.3 The Bauer–Brozoski Model

Bauer and Brozoski (Bauer et al. 1999) developed an animal model of tinnitus using the Jastreboff–Brennan model as a point of departure. In the Bauer– Brozoski model, which has been successfully applied using both rats and chinchillas, tinnitus is induced by a single unilateral sound exposure sufficient to produce a temporary threshold shift in the exposed ear without contralateral effects. The Bauer–Brozoski model is a derivative conditioned suppression method, but there are substantial differences between it and Jastreboff–Brennan method. In the Bauer–Brozoski method, subjects are required to perform a running operant task that establishes a steady-state baseline and continuously trains and tests stimulus-controlled behavior. In this way the model indicates the presence of tinnitus over any duration of time; using rats, for example, tinnitus was measured continuously over a 17-month period with no apparent loss of sensitivity (Bauer and Brozoski 2001).

Subjects are trained to press a lever for food pellets. Restricted food availability combined with a variable-interval reinforcement schedule in the conditioning chambers ensures stable and high rates of lever pressing throughout a test session. Free-field, low-intensity broad-band noise is always present in each conditioning chamber. This background sound is also the S+. Although food reinforcement is always available (there is no extinction), there are randomly inserted interruptions in the background sound. Typically there are 10 such interruptions per session, each 1 min in length. For two of the 10 interruptions the sound is turned off (S–). These may be considered suppression-training periods, as they conclude with a 1-s duration electric foot shock (Sr−). An Sr− occurs only if the subject lever presses in the sound-off period above a performance criterion level (typically R ≥ 0.2). The suppression-training periods insure that subjects pay close attention to the acoustic environment; this they communicate