Tinnitus, or “ringing in the ears,” is a common audiological complaint that is extremely heterogeneous in presentation, etiology, and severity.1 Tinnitus affects approximately 50 million Americans,2 with a similar worldwide prevalence.3 It is the number one service-related disability among U.S. veterans, affecting more than 2.17 million military members.4 There is also an increased prevalence of tinnitus in elderly populations, with estimates as high as 20% in adults over the age of 50.5 Tinnitus has many societal and economic impacts, with some studies estimating the annual tinnitus-related health care cost to be between $700 and $2,000 (USD) per individual.6,7
In addition to its high prevalence, the heterogeneity of tinnitus has complicated both research and clinical management of the disorder.1 Many documented causes of tinnitus include conductive and sensorineural hearing loss, ototoxicity, head and neck injury, and others.8 Tinnitus severity exists on a wide spectrum ranging from mildly bothersome to severely debilitating. The percept itself is also incredibly variable as some patients report a buzzing, whooshing, pure tone, or other indistinct sounds. Yet it remains unclear whether common or different mechanisms underlie tinnitus with different causes and clinical presentations.1 Importantly, there is neither a cure nor FDA-approved drugs for tinnitus. Many current clinical strategies are focused on alleviating the negative emotional effects of tinnitus without addressing the biological processes that underlie the phantom percept. Our review describes the current basic and clinical research of the physiological correlates of tinnitus and mechanism-driven drug development efforts.1
TINNITUS RESEARCH UPDATE
Tinnitus is the persistent, involuntary, subjective phantom percept of internally generated, indistinct, nonverbal noises and tones. In most cases, tinnitus is initiated by acquired hearing loss and maintained only when this loss is coupled with distinct neuronal changes in auditory and extra-auditory brain networks.1 The exact geometry of the electrical patterns of activity that are necessary and sufficient for the generation and maintenance of tinnitus lies within these networks, but the precise patterns and mechanisms remain unclear.1
In the last 30 years, tinnitus has gained more research attention. Recent progress in tinnitus research can be largely attributed to the development of tinnitus behavioral models in rodents beginning in the 1980s. Animal models are either operant or reflexive; both types are predicated on the idea that tinnitus alters the perception of silence. Operant models are based on the training of animals to behave differently in silence vs. noise. Reflexive models are based on differences in innate reflexes in response to acoustic stimulation or silence. While both models have significantly advanced tinnitus research, we propose that operant tinnitus animal models can assess the cognitive aspects of tinnitus and thus are more suitable for determining tinnitus mechanisms.
Utilizing tinnitus animal models, one of the earliest findings in tinnitus animal research is tinnitus-related neuronal hyperactivity in the dorsal cochlear nucleus (DCN),9,10 an auditory brainstem nucleus. A shift in the voltage dependence of KCNQ potassium channels was found to underlie the tinnitus-related hyperactivity and tinnitus vulnerability,11 while compensatory plasticity of HCN cation-specific channels may underlie resiliency to tinnitus after noise exposure.12 In addition to intrinsic neuronal excitability in the DCN, reduced GABAergic10 and glycinergic inhibitory transmission,13 as well as altered spike-timing plasticity between auditory and somatosensory inputs, contribute to tinnitus-related hyperexcitability.14 Tinnitus plasticity mechanisms have also been studied in other auditory nuclei. There have been somewhat conflicting findings in the inferior colliculus (IC). Namely, IC studies show increases, decreases, or no change in neuronal activity in the IC of tinnitus mice.15-20 Abnormal bursting and hyperactivity have been observed in the auditory thalamus.21 This aberrant thalamic firing has been linked to tinnitus22 and is hypothesized to play a role in the generation of pathological brain rhythms.23 Four main tinnitus correlates have been proposed in the auditory cortex: increased spontaneous firing, increased neural synchrony, increased gain, and tonotopic map reorganization. In addition to auditory areas, current research supports the involvement of non-auditory areas such as the parahippocampus and frontostriatal networks. Parahippocampal networks might play a role in the maintenance of tinnitus by encoding the memory of the tinnitus percept and subsequently reinforcing involuntary auditory memory and perception, while the pathological function of frontostriatal networks enhances tinnitus percepts by failing to suppress unwanted or insignificant percepts (gating). Overall, auditory, emotional, mnemonic, and attention networks are involved in the generation, maintenance, and severity of tinnitus.1
There are currently no FDA-approved therapeutics for tinnitus. The most commonly used therapies include sound-based therapies, such as hearing amplification and masking, and counseling or cognitive behavior therapy (CBT). These approaches are designed to decrease the awareness of the percept or manage the emotional effects of tinnitus but do not target the underlying pathophysiological mechanisms. Recently, significant progress has been made toward the development of device-based therapies such as bimodal (auditory and trigeminal or vagus nerve) stimulation, transcranial magnetic stimulation, and deep brain stimulation. These approaches are aimed to reverse pathogenic plasticity or promote corrective plasticity (rehabilitation) in the brain.
MECHANISM-DRIVEN TINNITUS DRUG DEVELOPMENT
We place a special emphasis on mechanism-driven drug development informed by basic research findings.1 Several compounds are under clinical or preclinical investigation for the treatment of tinnitus, including KCNQ potassium channel openers that aim to reduce hyperexcitability in the auditory brainstem, a Group II mGluR agonist to reduce hyperexcitability in the inferior colliculus, NMDAR channel antagonists to reduce excitotoxicity in the cochlea after noise exposure, a glutathione peroxidase (GPx) inhibitor, and a T-type calcium channel blocker to reduce inflammation after noise exposure and in subsequent tinnitus.
PATIENT STRATIFICATION, PRECISION MEDICINE, AND BEYOND
A crucial missing piece in tinnitus research is a mechanism-driven classification system that objectively measures tinnitus and accounts for the observed heterogeneity. Perhaps the biggest of these challenges is the lack of an objective tinnitus measurement.24,25 Current tinnitus diagnostic criteria rely on standard audiometry and self-report measures that subjectively assess how bothersome tinnitus is to the patient. The current classification of tinnitus patients also represents a significant challenge. The lack of effective patient stratification likely contributes to negative or conflicting clinical trial results. Given this heterogeneity, a neuroscience-based precision medicine approach will facilitate clinical trials, treatment, and cure. The use of objective neurophysiological measures (e.g., EEG, MRI, MEG, ABR) or biomarkers (e.g., blood or DNA sampling) may be more useful and reduce experimental variability. Taken together, the future of tinnitus research and drug development must include objective measures, mechanism-driven treatments, and precision medicine approaches.26
1. Henton A, Tzounopoulos T. What's the Buzz? The Neuroscience and the Treatment of Tinnitus. Physiol Rev. 2021.
2. Shargorodsky J, Curhan GC, Farwell WR. Prevalence and characteristics of tinnitus among US adults. The American journal of Medicine
3. McCormack A, Edmondson-Jones M, Somerset S, Hall D. A systematic review of the reporting of tinnitus prevalence and severity. Hearing Research
4. Affairs UDoV. Veterans Benefits Administration Reports: Compensation. Online. 2020.
5. Oosterloo BC, Croll PH, de Jong RJB, Ikram MK, Goedegebure A. Prevalence of Tinnitus in an Aging Population and Its Relation to Age and Hearing Loss. Otolaryngology-Head and Neck Surgery: Official Journal of American Academy of Otolaryngology-Head and Neck Surgery
6. Maes IH, Cima RF, Vlaeyen JW, Anteunis LJ, Joore MA. Tinnitus: a cost study. Ear and Hearing
7. Stockdale D, McFerran D, Brazier P, Pritchard C, Kay T, Dowrick C, et al. An economic evaluation of the healthcare cost of tinnitus management in the UK. BMC Health Serv Res
8. Coelho CB, Santos R, Campara KF, Tyler R. Classification of Tinnitus: Multiple Causes with the Same Name. Otolaryngologic clinics of North America
9. Brozoski TJ, Bauer CA, Caspary DM. Elevated fusiform cell activity in the dorsal cochlear nucleus of chinchillas with psychophysical evidence of tinnitus. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience
10. Middleton JW, Kiritani T, Pedersen C, Turner JG, Shepherd GM, Tzounopoulos T. Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(18):7601-6.
11. Li S, Choi V, Tzounopoulos T. Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(24):9980-5.
12. Li S, Kalappa BI, Tzounopoulos T. Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus. eLife
13. Wang H, Brozoski TJ, Turner JG, Ling L, Parrish JL, Hughes LF, et al. Plasticity at glycinergic synapses in dorsal cochlear nucleus of rats with behavioral evidence of tinnitus. Neuroscience
14. Marks KL, Martel DT, Wu C, Basura GJ, Roberts LE, Schvartz-Leyzac KC, et al. Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans. Sci Transl Med
15. Bauer CA, Turner JG, Caspary DM, Myers KS, Brozoski TJ. Tinnitus and inferior colliculus activity in chinchillas related to three distinct patterns of cochlear trauma. Journal of Neuroscience Research
16. Niu Y, Kumaraguru A, Wang R, Sun W. Hyperexcitability of inferior colliculus neurons caused by acute noise exposure. Journal of Neuroscience Research
17. Sturm JJ, Zhang-Hooks YX, Roos H, Nguyen T, Kandler K. Noise Trauma-Induced Behavioral Gap Detection Deficits Correlate with Reorganization of Excitatory and Inhibitory Local Circuits in the Inferior Colliculus and Are Prevented by Acoustic Enrichment. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience
18. Shaheen LA, Liberman MC. Cochlear Synaptopathy Changes Sound-Evoked Activity Without Changing Spontaneous Discharge in the Mouse Inferior Colliculus. Frontiers in Systems Neuroscience
19. Berger JI, Coomber B, Wells TT, Wallace MN, Palmer AR. Changes in the response properties of inferior colliculus neurons relating to tinnitus. Frontiers in Neurology
20. Ropp TJ, Tiedemann KL, Young ED, May BJ. Effects of unilateral acoustic trauma on tinnitus-related spontaneous activity in the inferior colliculus. Journal of the Association for Research in Otolaryngology: JARO
21. Kalappa BI, Brozoski TJ, Turner JG, Caspary DM. Single unit hyperactivity and bursting in the auditory thalamus of awake rats directly correlates with behavioural evidence of tinnitus. The Journal of Physiology
22. De Ridder D, Elgoyhen AB, Romo R, Langguth B. Phantom percepts: tinnitus and pain as persisting aversive memory networks. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(20):8075-80.
23. Llinás RR, Ribary U, Jeanmonod D, Kronberg E, Mitra PP. Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(26):15222-7.
24. Henry JA. “Measurement” of Tinnitus. Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2016;37(8):e276-85.
25. Jackson R, Vijendren A, Phillips J. Objective Measures of Tinnitus: a Systematic Review. Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2019;40(2):154-63.
26. Tzounopoulos T, Balaban C, Zitelli L, Palmer C. Towards a Mechanistic-Driven Precision Medicine Approach for Tinnitus. Journal of the Association for Research in Otolaryngology: JARO