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This year marks 25 years of tinnitus retraining therapy (TRT), the approach that aims to eliminate tinnitus as a problem by extinguishing functional connections between the auditory and the limbic and autonomic nervous systems to achieve habituation of tinnitus-evoked reactions and subsequently habituation of perception. TRT addresses directly decreased sound tolerance (DST) as well as tinnitus. TRT consists of counseling and sound therapy, both based on the neurophysiological model of tinnitus. The main goal of retraining counseling is to reclassify tinnitus into the category of a neutral stimulus, while the main goal of sound therapy is to decrease the strength of tinnitus-related neuronal activity. A unique aspect of TRT is that because treatment is aimed to work above the tinnitus source, and at connections linking the auditory and other systems in the brain, the etiology of tinnitus is irrelevant. Any type of tinnitus, as well as somatosounds, can be successfully treated by TRT. Over 100 publications can be found on Medline when using "tinnitus retraining therapy" as a search term. The majority of these publications indicate TRT offers significant help for about 80 % of patients. A randomized clinical trial showing the effectiveness of TRT has been published and another large study is in progress. The principles of the neurophysiological model of tinnitus, and consequently TRT, have not changed in over 25 years of use, but a number of changes have been introduced in TRT implementation. These changes include the recognition of the importance of conditioned reflexes and the dominant role of the subconscious pathways; the introduction of the concept of misophonia (i.e., negative reactions to specific patterns of sound) and the implementation of specific protocols for its treatment; greater emphasis on the concurrent treatment of tinnitus, hyperacusis, misophonia, and hearing loss; extensive modification of counseling; and refinements in sound therapy. The effectiveness of TRT has increased significantly during the past 25 years, presumably due to changes incorporated in its implementation. The main improvement has been to shorten the average time until seeing clear improvement from 1 year to 1 month, with a statistically significant improvement seen at, and after, 3 months. Furthermore, there is a higher effectiveness and a shorter treatment time for DST and an increased extent of help for hearing loss.

This chapter describes the application of decision and action rules mining to the problem area of tinnitus treatment and characterization. The chapter presents the process of a Tinnitus Retraining Therapy treatment protocol, which is to be automatized with classification and action rules. The tinnitus dataset collected at Emory University School of Medicine in Atlanta, as well as preprocessing steps performed on the data are described. Next, a series of experiments on association and action rule extraction are presented. Selected outcome rules are listed in a form of medical hypotheses. An analysis and interpretation of sample rules are provided together with their validation in accordance with expert medical knowledge.

Action rules should help in choosing treatment actions in the course of Tinnitus Retraining Therapy in subsequent visits. In order to understand the process of treatment and formulate appropriate data mining tasks in LISp-Miner, it is necessary to identify treatments actions taken by the doctor to improve tinnitus/hyperacusis patient’s condition.

This chapter presents the decision problem area which will be supported with a recommender system technology, that is, tinnitus diagnosis and treatment. It will introduce the problem of tinnitus and next, the successful method of treatment applied by doctor P. Jastreboff. At the end of this chapter major results from the treatment will be showed, along with possible new challenges, which can be handled with the help of information technology.

This book presented a process of analysis, design and prototype implementation of RECTIN recommender system, as a solution to the problem of supporting tinnitus treatment based on Tinnitus Retraining Therapy in a medical facility. Proposed approach in supporting physicians’ diagnosis and treatment decisions addresses scarcity of expert knowledge, time restrictions in today’s medical practice and the need for more efficient evaluation of different treatment methods. Such system can provide accurate support at any time, with full consideration of individual patient profiles, including: demographics, medical history, and tinnitus background.

Decreased sound tolerance (DST) is an underappreciated condition that affects the lives of a significant portion of the general population. There is lack of agreement regarding definitions, specific components, prevalence, methods of evaluation, and methods of treatment. Limited data are available on the results of treatments. Research is scant and constrained by the lack of an animal model. This article proposes a definition of DST and its division into hyperacusis and misophonia. The potential mechanisms of these phenomena are outlined, and the results of treatment performed at Emory University are presented. Out of 201 patients with DST, 165 (82%) showed significant improvement. Of 56 patients with hyperacusis (with or without misophonia), 45 (80%) showed significant improvement. This proportion was higher for the group with hyperacusis and concurrent misophonia (33 of 39, or 85%) and lower for patients with hyperacusis only (13 of 17, or 76%). Effectiveness of treatment for misophonia with or without hyperacusis was identical (152 of 184, 83% and 139 of 167, 83%, respectively, for misophonia accompanied by hyperacusis and for misophonia only). Even with current limited knowledge of DST, it is possible to propose specific mechanisms of hyperacusis and misophonia and, based on these mechanisms, to offer treatments in accordance with the neurophysiological model of tinnitus. These treatments are part of Tinnitus Retraining Therapy (TRT), which is aimed at concurrently treating tinnitus and DST and alleviating the effects of hearing loss. High effectiveness of the proposed treatments support the postulated mechanisms.

Our experience has revealed the following: (1) TRT is applicable for all types of tinnitus, as well as for decreased sound tolerance, with significant improvement of tinnitus occurring in over 80% of the cases, and at least equal success rate for decreased sound tolerance. (2) TRT can provide cure for decreased sound tolerance. (3) TRT does not require frequent clinic visits and has no side effects; however, (4) Special training of health providers involved in this treatment is required for this treatment to be effective.

The main objective of Tinnitus Retraining Therapy (TRT) is habituation of activation of the autonomic nervous system, evoked by signals present in the auditory pathways. Sound therapy aims at decreasing the strength of these signals. The same systems in the brain are involved in tinnitus and decreased sound tolerance, and the same basic neurophysiological mechanisms are utilised for decreasing the tinnitusrelated neuronal activity and, in case of hyperacusis, abnormally enhanced activity induced by external sounds. The similarity of TRT treatment between tinnitus and misophonia is even closer, as in both situations the goal is to achieve extinction of functional connections between the auditory and the limbic and autonomic nervous systems. The increased gain within the auditory pathways that are presumably responsible for hyperacusis could enhance the tinnitus signal, thus it is possible to expect coexistence of tinnitus and hyperacusis, and the predisposition of hyperacusis patients to develop tinnitus. As such, for some patients tinnitus and hyperacusis may be considered the double manifestation of the same internal phenomenon.

Clinical management for patients complaining of severe tinnitus has improved dramatically in the last 25 years. During that period of time, various methods of treatment have been introduced and are being used with varying degrees of success. One method that has received considerable attention is tinnitus retraining therapy (TRT). This method is being practiced by hundreds of clinicians worldwide, and retrospective clinical data indicate that TRT has been effective for the majority of patients. This article provides a guide for clinicians to evaluate their patients for treatment with TRT. Included in this guide is the expanded version of the TRT initial interview and specific instructions for the clinician administering the interview.

The effects of an extract from Ginkgo biloba, EGb 761, on tinnitus were tested using an animal model of tinnitus. Daily oral administration of EGb 761 in doses from 10 to 100 mg/ kg/day began 2 weeks before behavioral procedures and continued until the end of the experiment. Tinnitus was induced by daily administration of 321 mg/kg sodium salicylate s.c. (corresponding to 275 mg/kg/day of salicylate acid) in fourteen groups of pigmented rats, 6 animals/group. The results from salicylate- and EGb-761-treated animals were compared to control groups receiving either salicylate, saline, or EGb 761 only in doses of 100 mg/kg. Administration of EGb 761 resulted in a statistically significant decrease of the behavioral manifestation of tinnitus for doses of 25, 50 and 100 mg/kg/ day.

The evaluation of the spontaneous activity of 471 units from the external nucleus of the IC revealed that salicylate induces an increase of the spontaneous activity and the emergence of a bursting type of activity longer than 4 spikes. For sharply tuned units, the affected cells were from the frequency range of 10–16 kHz, which corresponds to the behaviorally measured pitch of salicylate-induced tinnitus in rats. An exogenous calcium supplement, provided under the conditions shown to attenuate the behavioral manifestation of salicylate-induced tinnitus, abolished the modification of the spontaneous activity induced by salicylate. Finally, profound changes of activity were observed for cells not responding to contralateral sound. We propose that the observed long bursts of discharges represent tinnitus-related neuronal activity. The results are consistent with the hypothesis that GABA-mediated disinhibition is involved in the processing of tinnitus-related neuronal activity.

The extended tinnitus database consisting of 758 patients with information repeated from the original database of 555 patients, along with the addition of visits and a new questionnaire, the Tinnitus Function Index and Emotion Indexing Questionnaire, is used to mine for knowledge. New patients in the extended database represent those patients that have completed the Tinnitus Function Index questionnaire (TFI) [10]. The patient visits are separated and used for mining and action rule discovery based on all features and treatment success indicators including several new features tied to emotions (based on a mapping from TFI to Emotion Indexing Questionnaire (EIQ) [14]; EIQ questionnaire is used by our team to build personalized classifiers for automatic indexing of music by emotions). We propose a link between TFI and EIQ leading to a creation of new features in the extended tinnitus database. Then, we extract knowledge from this new database in the form of association action rules to assist with understanding and validation of diagnosis and treatment outcomes.

To evaluate the reliability, dimensionality, predictive validity, construct validity, and sensitivity to change of the THI-12 total and sub-scales as diagnostic aids to describe and quantify tinnitus-evoked reactions and evaluate treatment efficacy.Explorative analysis of the German tinnitus handicap inventory (THI-12) to assess potential sensitivity to tinnitus therapy in placebo-controlled randomized studies. Correlation analysis, including Cronbach's coefficient α and explorative common factor analysis (EFA), was conducted within and between assessments to demonstrate the construct validity, dimensionality, and factorial structure of the THI-12.N = 618 patients suffering from subjective tinnitus who were to be screened to participate in a randomized, placebo-controlled, 16-week, longitudinal study.The THI-12 can reliably diagnose tinnitus-related impairments and disabilities and assess changes over time. The test-retest coefficient for neighboured visits was r0.69, the internal consistency of the THI-12 total score was α ≤ 0.79 and α ≤ 0.89 at subsequent visits. Predictability of THI-12 total score and overall variance increased with successive measurements. The three-factorial structure allowed for evaluation of factors that affect aspects of patients' health-related quality of life.The THI-12, with its three-factorial structure, is a simple, reliable, and valid instrument for the diagnosis and assessment of tinnitus and associated impairment over time.

Tinnitus problems affect a significant portion of the population and are difficult to treat. Sound therapy for Tinnitus is a promising, expensive, and complex treatment, where the complete process may span from several months to a couple of years. The goal of this research is to explore different combinations of important factors leading to a significant recovery, and their relationships to different category of Tinnitus problems. Our findings are extracted from the data stored in a clinical database, where confidential information had been stripped off. The domain knowledge spans different disciplines such as otology as well as audiology. Complexities were encountered with temporal data and text data of certain features. New temporal features together with rule generating techniques and clustering methods are presented with a ultimate goal to explore the relationships among the treatment factors and to learn the essence of Tinnitus problems.

1. Tinnitus Retraining Therapy (TRT) is strictly based on the neurophysiological model of tinnitus. 2. Tinnitus is a phantom auditory perception, i.e. perception of tinnitus is not linked to any vibratory activity within the cochlea. 3. The model postulates that it is necessary to include interconnections within a network of systems in the brain in the study and treatment of tinnitus. 4. The auditory system, while needed for perception of tinnitus, is secondary for clinically relevant tinnitus (i.e. tinnitus which is bothersome to the extent of requiring treatment). 5. The limbic and autonomic nervous systems are the main systems responsible for negative tinnitus-evoked reactions. 6. Tinnitus is frequently accompanied by a decreased sound tolerance, consisting of hyperacusis and misophonia. 7. Hyperacusis results from an increased gain within the auditory pathways and is determined solely by physical characteristics of sound (i.e. its intensity and spectrum). 8. Misophonia results from enhanced functional connections between the auditory and the limbic and autonomic nervous systems, and reactions occur to specific patterns of sound, with the total spectral energy being secondary or irrelevant. 9. In misophonia, the meaning of sound and an ­individual’s past history of encountering it is crucial, with the auditory characteristics of the sound playing a secondary role. 10. There are two loops in network processing tinnitus signal: a. High loop, which involves cognitive processing of the signal and which is dominant at the initial stages of tinnitus. b. Low, subconscious loop, which appears to become dominant in chronic tinnitus. Connections within the neural networks that are involved in the adverse effects of tinnitus are governed by the principles of conditioned reflexes. 11. The primary goal of TRT is habituation of reactions evoked by tinnitus. 12. Habituation is initiated and further facilitated using the method of modified passive extinction of the conditioned reflexes and involves: a. Teaching/counseling aimed at reclassification of the tinnitus signal to the category of neutral stimuli. b. Sound therapy, which decreases the strength of the tinnitus signal by increasing the level of background neuronal activity in the auditory system achieved by providing an enhanced sound background. 13. Habituation of perception happens automatically once sufficient level of habituation of reactions is achieved. 14. Decreased sound tolerance must be treated concurrently with tinnitus. 15. Different protocols must be used for hyperacusis than for misophonia. 16. A specific variant of treatment, related to ­classifying a patient to one of 5 categories, is determined by the following factors: a. Impact of tinnitus on patients’ lives and/or duration of clinically significant tinnitus. b. The presence of hyperacusis. c. The presence and significance of hearing loss. d. Prolonged exacerbation of tinnitus/hyperacusis by sound. 17. Misophonia is treated independently by specific protocols concurrently with tinnitus, hyperacusis, and hearing loss. 18. Results from many centers have confirmed the effectiveness of the tinnitus retraining therapy (TRT) for tinnitus, reporting a success rate of more than 80%. 19. Specific studies performed to assess the stability of improvement after 3 and 5 years revealed that impro-vement continues to be present with patients over time. These studies show a trend of ­continuing improvement, even after ending the treatment. 20. Prevention of clinically significant tinnitus or potential worsening of already existing tinnitus could be achieved by: a. Avoidance of silence and providing enriched sound environment. b. Avoidance of negative counseling and ­providing proper information in advance. 21. Certain populations are at high risk of developing clinically significant tinnitus, such as military ­personnel, police officers and firefighters, and patients who are going to have ear-related surgery. Providing them with a proper short informational session about tinnitus would significantly decrease the risk of developing bothersome tinnitus. People will still hear tinnitus, but it will not be a problem for them.

In two behavioral experiments, normal hearing or salicylate-induced phantom auditory perception were investigated in young pigmented rats. Twenty-four hours prior to training in Experiment 1, 45 preweanling pups (14–21 days of age) were exposed to continuous background noise. They were injected with sodium salicylate or saline either before or after training to suppress approach responses to a lactating dam during noise offset periods. The sequence of injection initiation affected acquisition and extinction rates, and the oldest subjects behaved similarly to adults reported in studies of salicylate-induced auditory effects. Adapting the task in Experiment 2 for 18 postweanling pups 32 days of age produced greater suppression and prolonged extinction when salicylate was administered prior to both acquisition and extinction sessions, whereas subjects injected with saline before training and salicylate before extinction showed rapid recovery from suppression. The experiments support the notion that the auditory system undergoes functionally important change at around 15–16 days of age.

This paper presents a neurophysiological approach to tinnitus and discusses its clinical implications. A hypothesis of discordant damage of inner and outer hair cells systems in tinnitus generation is outlined. A recent animal model has facilitated the investigation of the mechanisms of tinnitus and has been further refined to allow for the measurement of tinnitus pitch and loudness. The analysis of the processes involved in tinnitus detection postulates the involvement of an abnormal increase of gain within the auditory system. Moreover, it provides a basis for treating patients with hyperacusis, which we are considering to be a pre-tinnitus state. Analysis of the process of tinnitus perception allows for the possibility of facilitating the process of tinnitus habituation for the purpose of its alleviation. The combining of theoretical analysis with clinical findings has resulted in the creation of a multidisciplinary Tinnitus Centre. The foundation of the Centre focuses on two goals: the clinical goal is to remove tinnitus perception from the patient's consciousness, while directing research toward finding a mechanism-based method for the suppression of tinnitus generators and processes responsible for enhancement of tinnitus-related neuronal activity.

Electrical stimulation through a round window electrode has been evaluated in 9 patients with unilateral deafness and severe tinnitus. Three subjects were permanently implanted with positive long lasting results. Analysis of the threshold of sound perception, tinnitus suppression and auditory discomfort levels as a function of current frequency revealed the advantage of low frequency stimulation. In 2 patients the loudness of electrically evoked sound perception was balanced against tones in the hearing ear. Our results can be interpreted as indicating that processes other than auditory masking are responsible for electrical tinnitus suppression.

Medical records contain feature values on specific dates, which brings very unstable sampling rate. Therefore popular temporal features, which have been successfully applied to sound data, failed to fully describe the vita behaviors of features and factors of patient and treatment. The authors developed a flexible temporal feature retrieval system based on grouping of similar visiting patterns with connection to an action-rules engine and observed interesting and useful results about how the changes of treatment factors affects the changes of recover.

Lyme disease-induced hyperacusis can be an intensely disabling, chronic condition that is accompanied by posttraumatic stress disorder-like psychobehavioral sequelae. The authors describe effective treatment of 2 patients with carbamazepine. Speculations regarding a mode of action are offered.

Both tinnitus masking (TM) and tinnitus retraining therapy (TRT) can be effective therapies for amelioration of tinnitus. TM may be more effective for patients in the short term, but with continued treatment TRT may produce the greatest effects.Although TM and TRT have been used for many years, research has not documented definitively the efficacy of these methods. The present study was a controlled clinical trial to prospectively evaluate the clinical efficacy of these two methods for US military veterans with severe tinnitus.Over 800 veterans were screened to ensure that enrolled patients had tinnitus of sufficient severity to justify 18 months of individualized treatment. Qualifying patients (n=123) were placed quasi-randomly (alternating placement) into treatment with either TM or TRT. Treatment was administered at 0, 3, 6, 12, and 18 months. Outcomes of treatment were evaluated primarily using three self-administered tinnitus questionnaires (Tinnitus Handicap Inventory, Tinnitus Handicap Questionnaire, Tinnitus Severity Index).Findings are presented from the three written questionnaires with respect to three categories of patients: describing tinnitus as a 'moderate,' 'big,' and 'very big' problem at baseline. Based on effect sizes, both groups showed considerable improvement overall. In general, TM effects remained fairly constant over time while TRT effects improved incrementally. For the patients with a 'moderate' and 'big' problem, TM provided the greatest benefit at 3 and 6 months; benefit to these TRT patients was slightly greater at 12 months, and much greater at 18 months. For patients with a 'very big' problem, TM provided the greatest benefit at 3 months. For these latter patients, results were about the same between groups at 6 months, and improvement for TRT was much greater at 12 months, with further gains at 18 months.

A controlled clinical study was conducted to evaluate prospectively the clinical efficacy of tinnitus masking (TM) and tinnitus retraining therapy (TRT) in military veterans having clinically significant tinnitus. Qualifying patients were placed into the two groups in an alternating manner (to avoid selection bias), and treatment was administered at 0, 3, 6, 12, and 18 months. Outcomes of treatment were evaluated using three self-administered tinnitus questionnaires (Tinnitus Handicap Inventory, Tinnitus Handicap Questionnaire, Tinnitus Severity Index) and the verbally administered TRT interview forms. Findings are presented from the three written questionnaires, and from two of the interview questions (percentage time aware of, and annoyed by, tinnitus). Outcomes were analyzed on an intent-to-treat basis, using a multilevel modeling approach. Of the 123 patients enrolled, 118 were included in the analysis. Both groups showed significant declines (improvements) on these measures, with the TRT decline being significantly greater than for TM. The greater declines in TRT compared to TM occurred most strongly in patients who began treatment with a "very big" tinnitus problem. When patients began treatment with a "moderate" tinnitus problem, the benefits of TRT compared to TM were more modest.

Tinnitus retraining therapy (TRT) is a method for treating tinnitus and decreased sound tolerance, based on the neurophysiological model of tinnitus. This model postulates involvement of the limbic and autonomic nervous systems in all cases of clinically significant tinnitus and points out the importance of both conscious and subconscious connections, which are governed by principles of conditioned reflexes. The treatments for tinnitus and misophonia are based on the concept of extinction of these reflexes, labeled as habituation. TRT aims at inducing changes in the mechanisms responsible for transferring signal (i.e., tinnitus, or external sound in the case of misophonia) from the auditory system to the limbic and autonomic nervous systems, and through this, remove signal-induced reactions without attempting to directly attenuate the tinnitus source or tinnitus/misophonia-evoked reactions. As such, TRT is effective for any type of tinnitus regardless of its etiology. TRT consists of: (1) counseling based on the neurophysiological model of tinnitus, and (2) sound therapy (with or without instrumentation). The main role of counseling is to reclassify tinnitus into the category of neutral stimuli. The role of sound therapy is to decrease the strength of the tinnitus signal. It is crucial to assess and treat tinnitus, decreased sound tolerance, and hearing loss simultaneously. Results from various groups have shown that TRT can be an effective method of treatment.

This chapter focuses on measurement and models of a clinical symptom called tinnitus. Tinnitus is defined here as the perception of sound originating in the head. The justification motivating this definition is presented later.

Validity of the neurophysiological model of tinnitus (Jastreboff, 1990), outlined in this paper, was tested on data from multicenter trial of tinnitus masking (Hazell et al., 1985). Minimal masking level, intensity match of tinnitus, and the threshold of hearing have been evaluated on a total of 382 patients before and after 6 months of treatment with maskers, hearing aids, or combination devices. The data has been divided into categories depending on treatment outcome and type of approach used. Results of analysis revealed that: i) the psychoacoustical description of tinnitus does not possess a predictive value for the outcome of the treatment; ii) minimal masking level changed significantly depending on the treatment outcome, decreasing on average by 5.3 dB in patients reporting improvement, and increasing by 4.9 dB in those whose tinnitus remained the same or worsened; iii) 73.9% of patients reporting improvement had their minimal masking level decreased as compared with 50.5% for patients not showing improvement, which is at the level of random change; iv) the type of device used has no significant impact on the treatment outcome and minimal masking level change; v) intensity match and threshold of hearing did not exhibit any significant changes which can be related to treatment outcome. These results are fully consistent with the neurophysiological interpretation of mechanisms involved in the phenomenon of tinnitus and its alleviation.

• Quinine ingestion reportedly induces tinnitus in humans. To expand our salicylate-based animal model of tinnitus, a series of conditioned suppression experiments was performed on 54 male-pigmented rats using quinine injections to induce tinnitus. Quinine induced changes in both the extent of suppression and recovery of licking, which followed a pattern that paralleled those produced after salicylate injections, and which may be interpreted as the result of tinnitus perception in animals. These changes depended on the dose and time schedule of quinine administration. Additionally, the calcium channel blocker, nimodipine, abolished the quinine-induced effect in a dose-dependent manner. (Arch Otolaryngol Head Neck Surg. 1991;117:1162-1166)

Phantom auditory perception--tinnitus--is a symptom of many pathologies. Although there are a number of theories postulating certain mechanisms of its generation, none have been proven yet. This paper analyses the phenomenon of tinnitus from the point of view of general neurophysiology. Existing theories and their extrapolation are presented, together with some new potential mechanisms of tinnitus generation, encompassing the involvement of calcium and calcium channels in cochlear function, with implications for malfunction and aging of the auditory and vestibular systems. It is hypothesized that most tinnitus results from the perception of abnormal activity, defined as activity which cannot be induced by any combination of external sounds. Moreover, it is hypothesized that signal recognition and classification circuits, working on holographic or neuronal network-like representation, are involved in the perception of tinnitus and are subject to plastic modification. Furthermore, it is proposed that all levels of the nervous system, to varying degrees, are involved in tinnitus manifestation. These concepts are used to unravel the inexplicable, unique features of tinnitus and its masking. Some clinical implications of these theories are suggested.

Tinnitus Retraining Therapy (TRT) is a structured method of tinnitus treatment that has been performed since 1990. The TRT Initial Interview form was developed to guide clinicians in obtaining essential information from patients that would specify treatment needs. The TRT Follow-up Interview form is similar to the initial interview form and is designed to evaluate outcomes of treatment. The clinician administers these forms verbally. The forms have been used in a highly abbreviated format with the potential for inconsistent interview administration between examiners. This project was to expand the forms to provide specific wording for each question. The expanded forms are presented in this article, and the intent of each question is explained. Standardized administration of these interview forms will facilitate greater uniformity in the initial evaluation and outcomes analyses of patients treated with TRT.

Subjective tinnitus remains obscure, widespread, and without apparent cure. In the absence of a suitable animal model, past investigations took place in humans, resulting in studies that were understandably restricted by the nature of human investigation. Within this context, the development of a valid animal model would be considered a major breakthrough in this field of investigation. Our results showed changes in the spontaneous activity of single neurons in the inferior colliculus, consistent with abnormally increased neuronal activity within the auditory pathways after manipulations known to produce tinnitus in man. A procedure based on a Pavlovian conditioned suppression paradigm was recently developed that allows us to measure tinnitus behaviorally in conscious animals. Accordingly, an animal model of tinnitus is proposed that permits tests of hypotheses relating to tinnitus generation, allowing the accommodation of interventional strategies for the treatment of this widespread auditory disorder.

Background Neramexane is a new substance that exhibits antagonistic properties at α9α10 cholinergic nicotinic receptors and N-methyl-D-aspartate receptors, suggesting potential efficacy in the treatment of tinnitus. Methods A total of 431 outpatients with moderate to severe subjective tinnitus (onset 3-18 months before screening) were assigned randomly to receive either placebo or neramexane mesylate (25 mg/day, 50 mg/day and 75 mg/day) for 16 weeks, with assessment at 4-week intervals. The primary (intention-to-treat) efficacy analysis was based on the change from baseline in Week 16 in the total score of the adapted German short version of the validated Tinnitus Handicap Inventory questionnaire (THI-12). Results Compared with placebo, the largest improvement was achieved in the 50 mg/d neramexane group, followed by the 75 mg/d neramexane group. This treatment difference did not reach statistical significance at the pre-defined endpoint in Week 16 (p = 0.098 for 50 mg/d; p = 0.289 for 75 mg/d neramexane), but consistent numerical superiority of both neramexane groups compared with placebo was observed. Four weeks after the end of treatment, THI-12 scores in the 50 mg/d group were significantly better than those of the controls. Secondary efficacy variables supported this trend, with p values of < 0.05 for the 50 mg/d neramexane group associated with the functional-communicational subscores of the THI-12 and the assessments of tinnitus annoyance and tinnitus impact on life as measured on an 11-point Likert-like scale. No relevant changes were observed for puretone threshold, for tinnitus pitch and loudness match, or for minimum masking levels. The 25 mg/d neramexane group did not differ from placebo. Neramexane was generally well tolerated and had no relevant influence on laboratory values, electrocardiography and vital signs. Dizziness was the most common adverse event and showed a clear dose-dependence. Conclusions This study demonstrated the safety and tolerability of neramexane treatment in patients with moderate to severe tinnitus. The primary efficacy variable showed a trend towards improvement of tinnitus suffering in the medium- and high-dose neramexane groups. This finding is in line with consistent beneficial effects observed in secondary assessment variables. These results allow appropriate dose selection for further studies. Trial Registration ClinicalTrials.gov NCT00405886