Dr Hashir Aazh, Audiologist
Director, Hashir International Institute, London, United Kingdom
President, 4th World Tinnitus Congress and 15th International Tinnitus Seminar (London, 2027)
Tinnitus is most commonly described as the perception of sound in the absence of an external source. However, this definition remains conceptually incomplete. A more precise working formulation treats tinnitus as a consciously recognised, non-semantic, sound or sound-like experience occurring in wakeful consciousness, persisting beyond fleeting moments, and becoming experientially salient. This distinction is important, as it separates the percept itself from the distress it may evoke, allowing tinnitus to be conceptualised as a first-person phenomenon that is accessible primarily through self-report rather than objective measurement. Consequently, the absence of report cannot be taken as definitive evidence of absence, as tinnitus may exist without being consciously recognised or articulated.
The 2nd International Conference on Pharmacology and Gene Therapy for Tinnitus, organised by the Hashir International Institute, brought together researchers from neuroscience, pharmacology, and clinical science to explore emerging mechanistic insights and potential pharmacological approaches to tinnitus. Within this context, there was increasing recognition that tinnitus cannot be adequately explained by purely peripheral models.
For pharmacology, this has important implications. If tinnitus reflects the conscious registration of internally generated neural activity, then it cannot be fully understood, or treated, as a disorder of the ear alone. Instead, it requires a framework that spans peripheral input, central neural processing, and the mechanisms through which activity becomes perception.
Recent work in auditory neuroscience supports a systems-level account of tinnitus involving dysregulated activity across distributed networks (Eggermont, 2015; Knipper et al., 2020). These include auditory pathways as well as thalamic, limbic, and cortical systems associated with attention, memory, and emotional salience. Within this framework, tinnitus is increasingly understood as a consequence of maladaptive plasticity, in which changes in neural circuits following altered sensory input lead to persistent, self-sustaining patterns of activity.
A key concept in this context is central gain. Following reduced or degraded auditory input, such as hearing loss, the auditory system may increase its sensitivity in an attempt to compensate (Noreña, 2011; Schaette and Kempter, 2006). While adaptive in principle, excessive or poorly regulated gain can amplify spontaneous neural activity, allowing it to enter conscious awareness as tinnitus. This process is thought to involve interactions across multiple levels of the auditory system, including thalamocortical circuits that regulate neural synchrony and oscillatory activity (De Ridder et al., 2015).
At the cellular level, these changes can be understood in terms of altered excitation–inhibition balance. In normal auditory processing, inhibitory neurotransmission, primarily mediated by gamma-aminobutyric acid (GABA), plays a central role in controlling neural gain and suppressing irrelevant activity. When this inhibitory control is reduced, neural systems may become hyperexcitable, leading to increased spontaneous firing and synchronisation.
One mechanism contributing to this imbalance involves disruption of chloride homeostasis. The potassium–chloride cotransporter 2 (KCC2) maintains low intracellular chloride levels, enabling GABA to exert its inhibitory, hyperpolarising effect (Kahle et al., 2015). Following acoustic trauma, reduced expression of KCC2 has been observed in auditory pathways, leading to elevated intracellular chloride concentrations. Under these conditions, GABAergic signalling may become less effective, or even depolarising, thereby weakening inhibition and promoting network instability (Parameshwarappa et al., 2024).
On the excitatory side, glutamatergic mechanisms also play a role. Alterations in glutamate signalling, including pathways involving metabotropic glutamate receptor 5 (mGluR5), have been linked to auditory hypersensitivity in experimental models (Auerbach et al., 2021). Pharmacological modulation of these pathways has been shown to normalise exaggerated responses, highlighting their potential relevance as therapeutic targets. Despite these advances, translation into clinical treatments remains limited. Animal models can demonstrate neural hyperactivity and altered gain, but they cannot capture the subjective experience that defines tinnitus. This creates a fundamental translational challenge: linking measurable neural processes to a condition that is defined by conscious perception.
Clinical studies face similar difficulties. Tinnitus is highly heterogeneous, both in its underlying mechanisms and in its presentation. Similar perceptual experiences may arise from different biological pathways, including noise-induced changes, stress-related modulation of neural activity, neurodevelopmental factors, and, in some cases, mechanisms associated with pain hyperacusis (Manohar et al., 2023). This heterogeneity contributes to variable treatment outcomes and complicates the design of pharmacological trials.
These challenges suggest that future progress will depend on more stratified approaches. Rather than seeking a single treatment for tinnitus, pharmacological research may need to focus on identifying subtypes based on underlying mechanisms. Advances in neuroimaging, electrophysiology, and computational modelling may support this shift by enabling more precise characterisation of neural activity associated with different forms of tinnitus. Importantly, pharmacological approaches should not be viewed in isolation. Behavioural and psychological interventions act on complementary aspects of the same system, influencing attention, interpretation, and learning processes that shape how tinnitus is experienced. Given that tinnitus arises at the interface of neural activity and conscious awareness, combining pharmacological and behavioural approaches is likely to be essential.
The absence of licensed pharmacological treatments does not reflect a lack of relevant targets, but rather the complexity of the condition. Patient priorities consistently highlight the desire for interventions that directly modify or suppress the tinnitus percept (Hall et al., 2013), reinforcing the need for continued investment in pharmacological research.
Momentum in this field is growing. The next major opportunity to bring together researchers across disciplines will be the 4th World Tinnitus Congress and 15th International Tinnitus Seminar, taking place in London in 2027 (https://wtc2027.co.uk/). This meeting will provide a platform to align mechanistic insights with translational strategies and accelerate progress toward clinically meaningful interventions.
Tinnitus presents a unique challenge for pharmacology. It is not defined solely by measurable pathology, but by the conscious perception of internally generated neural activity. As such, it sits at the boundary between neurobiology and subjective experience. Addressing this challenge will require integrating molecular, systems, and experiential perspectives into a coherent framework.
In doing so, tinnitus may also offer a broader opportunity. It provides a model for understanding how neural activity becomes perception, and how that perception might be modified through targeted intervention. Progress in this field could therefore extend beyond tinnitus itself, informing pharmacological approaches to other conditions in which neural dynamics and conscious experience are closely linked.
For a more in-depth exploration of these findings, see: Aazh et al. (2026), Advances in Pharmacological Approaches to Tinnitus and Hyperacusis: Insights into Mechanisms, Biomarkers, and Clinical Heterogeneity from an International Scientific Meeting, published in Brain Sciences. https://doi.org/10.3390/brainsci16050450
References
Auerbach, B. D., Manohar, S., Radziwon, K., & Salvi, R. (2021). Auditory hypersensitivity and processing deficits in a rat model of fragile X syndrome. Neurobiology of Disease, 161, 105541. https://doi.org/10.1016/j.nbd.2021.105541
De Ridder, D., Vanneste, S., Langguth, B., & Llinas, R. (2015). Thalamocortical dysrhythmia: A theoretical update in tinnitus. Frontiers in Neurology, 6. https://doi.org/10.3389/fneur.2015.00124
Eggermont, J. J. (2015). The auditory cortex and tinnitus – a review of animal and human studies. European Journal of Neuroscience, 41(5), 665–676. https://doi.org/10.1111/ejn.12759
Hall, D. A., Mohamad, N., Firkins, L., Fenton, M., & Stockdale, D. (2013). Identifying and prioritising unmet research questions for people with tinnitus. Clinical Investigation, 3(1), 21–28. https://doi.org/10.4155/cli.12.129
Kahle, K. T., Khanna, A. R., Alper, S. L., Adragna, N. C., Lauf, P. K., Sun, D., & Delpire, E. (2015). K-Cl cotransporters, cell volume homeostasis, and neurological disease. Trends in Molecular Medicine, 21(8), 513–523. https://doi.org/10.1016/j.molmed.2015.05.008
Knipper, M., Van Dijk, P., Schulze, H., et al. (2020). The neural bases of tinnitus: Lessons from deafness and cochlear implants. The Journal of Neuroscience, 40(38), 7190–7202. https://doi.org/10.1523/JNEUROSCI.1314-19.2020
Manohar, S., Chen, G.-D., Li, L., Liu, X., & Salvi, R. (2023). Chronic stress induced loudness hyperacusis, sound avoidance and auditory cortex hyperactivity. Hearing Research, 431, 108726. https://doi.org/10.1016/j.heares.2023.108726
Noreña, A. J. (2011). An integrative model of tinnitus based on a central gain controlling neural sensitivity. Neuroscience & Biobehavioral Reviews, 35(5), 1089–1109. https://doi.org/10.1016/j.neubiorev.2010.11.003
Parameshwarappa, V., Siponen, M. I., Watabe, I., et al. (2024). Noise-induced hearing loss alters potassium-chloride cotransporter KCC2 and GABA inhibition in auditory centres. Scientific Reports, 14, 10689. https://doi.org/10.1038/s41598-024-60858-1
Schaette, R., & Kempter, R. (2006). Development of tinnitus-related neuronal hyperactivity through homeostatic plasticity after hearing loss. European Journal of Neuroscience, 23(11), 3124–3138. https://doi.org/10.1111/j.1460-9568.2006.04774.x
