Exploring the Underlying Causes and Sustaining Factors of Subjective Tinnitus: An Insight into its Pathophysiology

This article explores the underlying causes and sustaining factors of subjective tinnitus, providing insight into its pathophysiology. It aims to raise awareness about the mechanisms that contribute to the development and maintenance of tinnitus and provide a deeper understanding of this condition

Exploring the Underlying Causes and Sustaining Factors of Subjective Tinnitus

Tinnitus is a condition where people hear a sound in their ears, but there is no actual external noise causing it. This phantom sound is a common problem, and researchers are trying to figure out what causes it. This study looked at published research to understand what we know about tinnitus and what still needs to be studied. The researchers found that tinnitus is a complex issue that affects both the hearing system and other parts of the brain. They concluded that it is important to continue to study tinnitus in order to better treat it.

This is the more indepth version of Does Tinnitus Affect the Brain?

Researched Fact Checked: Ncbi and Frontiers

Finding Relevant Literature for Tinnitus Research: A Guide to Identifying and Choosing Appropriate Sources

Tinnitus is a subjective phantom sound perceived in the absence of external or internal stimuli and affects a large number of people worldwide. Its classification system is based on various criteria such as causes, comorbidities, symptom characteristics, and psychological burden. The most common form of tinnitus is associated with a hearing loss and is further classified into primary (associated with sensorineural hearing loss or idiopathic) and secondary (related to other causes such as organic). Tinnitus duration (acute or chronic) and the description of the tinnitus sound (continuous or intermittent, pulsatile or non-pulsatile) are also used in classifying tinnitus.

The functional and psychological impact of tinnitus are also important factors, and various questionnaires have been designed to assess this, such as the Tinnitus Handicap Inventory, Tinnitus Questionnaire, Tinnitus Functional Index, and Tinnitus Primary Function Questionnaire.

The origin of tinnitus is related to aberrant neural activity at certain levels of the auditory system, and tinnitus can be classified as peripheral or central depending on the level of aberrant neural activity. The distinction between peripheral and central tinnitus is not completely independent, and the latest research suggests that tinnitus may result from a combination of both peripheral and central mechanisms. The exact pathophysiology of tinnitus remains unclear and is the subject of ongoing research.

In 2017, a literature search was done to gather information about the pathophysiology of subjective chronic tinnitus. Three literature search platforms were used - PubMed, Medline and Web of Science - and the search terms pathophysiology and subjective chronic tinnitus were used. The search resulted in 373 records, after removing duplicates, 168 records were left for further review. After screening, 121 full texts were eligible for the review, and 50 additional records were found through a manual search. The information was then extracted and assessed by two team members, and in case of disagreement, a third member was consulted.

Demographic Traits Reflecting the Pathophysiology of Tinnitus

Studies have indicated that in about 30% of tinnitus cases, the cause is undetermined. Tinnitus is commonly associated with noise-induced hearing loss and presbycusis, and about 90% of people with tinnitus in the UK have some form of hearing loss. Other risk factors for tinnitus have been identified, such as vascular disease, hypertension, diabetes, autoimmune disorders, head injury, and degenerative neural disorders.

Contrasting Neurophysiological Findings in Animals and Humans

This section is discussing the comparison between animal and human studies on the pathophysiology of tinnitus. The advantages of using animal models in tinnitus research include the ability to control the etiology and to apply a wide range of experimental tools, but there are also disadvantages such as the lack of a standardized animal model and the difficulty in translating findings from animal models to humans. Animal studies typically focus on tinnitus as a consequence of acute peripheral lesion associated with severe hearing loss, while human neuroimaging studies tend to emphasize the role of auditory thalamus and auditory cortex in the chronification and maintenance of tinnitus. The limitations of measuring techniques in human studies also bring important caveats for drawing analogies between animal and human findings.

The current understanding of tinnitus suggests that it is a complex interaction between peripheral and central mechanisms within the auditory pathway. It is widely believed that tinnitus reflects a pathology of neural plasticity with both a molecular and systemic component. The molecular component has a cochlear origin and is related to the initiation phase of tinnitus, while the systemic component has a central aspect associated with the long-term maintenance of tinnitus.

It has been suggested that peripheral tinnitus may originate from the dysfunction of cochlear outer hair cells (OHCs) leading to increased spontaneous cochlear activity. Meanwhile, central tinnitus is mediated by the neuronal activity in the auditory centers. This central activity is often triggered by a reduction of cochlear activity, but damage to cochlear tissues is not necessary to produce central changes related to tinnitus.

Locations of Tinnitus Origin: A Study of its Generation

Based on these observations, tinnitus is classified into three distinct subtypes: cochlear tinnitus, peripheral-dependent central tinnitus, and peripheral-independent central tinnitus. Cochlear tinnitus is generated by aberrant activity in the inner ear, which is propagated through the cochlear nerve and the central auditory pathway. Peripheral-dependent central tinnitus is associated with cochlear spontaneous activity, while peripheral independent central tinnitus is independent from cochlear spontaneous activity.

In conclusion, the generation of tinnitus is a complex process that involves both peripheral and central mechanisms within the auditory pathway. Further research is needed to fully understand the mechanisms behind tinnitus and to develop effective treatments.

Exploring the Cellular Processes Behind Tinnitus

There are several cellular mechanisms that are believed to contribute to the development of tinnitus. Some of these mechanisms are the loss of outer hair cell (OHC) electromotility, damage to the stereocilia bundle, death of OHCs or inner hair cells (IHCs), or rupture of the basilar membrane. This can lead to a decrease in neuronal output from the cochlea to the brain and the potential for compensation mechanisms in the brain.

Examining the Role of Tectorial Membrane in Tinnitus

Change in the position of the tectorial membrane can also be a pathophysiological trigger for tinnitus. For example, intense noise exposure can alter the rootlets of stereocilia, leading to stiffness and an increase in cochlear spontaneous activity.

Investigating the Function of Outer Hair Cells (OHCs) in Tinnitus

Damage to the stereocilia of OHCs is another potential trigger for tinnitus, often following an intense noise exposure. The initiation of the pathological process begins at the stereocilia of OHCs, with two fundamental processes being damaged by the noise: intracellular calcium levels and biochemical changes of their structural proteins.

Exploring the Interaction between Inner Hair Cells (IHCs) and Cochlear NMDA Receptors in Tinnitus

The N-methyl-D-aspartate (NMDA) receptor has also been found to play a role in noise-induced tinnitus. NMDA receptors predominate on the modiolar side of IHCs, and an increase in glutamate levels derived from IHCs can activate these receptors and lead to excessive calcium influx in the dendrites of the spiral ganglion neurons, resulting in an over-excitation of NMDA-receptors and tinnitus.

Understanding the Impact of Endocochlear Potential Increase on Tinnitus

An increase in the endocochlear potential can also depolarize IHCs, leading to a sequence of events that includes the opening of voltage-gated calcium channels, an intracellular influx of calcium, and the fusion of the synaptic ribbon to the plasmatic membrane, resulting in glutamate release and depolarization of cochlear fibers. This process can be induced by acute noise trauma that reduces the opening probability of OHC's mechano-electrical transduction channels, leading to an increase in the endocochlear potential.

Finally, biochemical changes, such as the heat-shock protein group (stress proteins) that interacts with structural proteins of hair cells, can also contribute to the development of tinnitus. Any disturbance that causes a deficient heat-shock protein system response can lead to the onset of tinnitus.

Investigating the Role of Cochlear Synaptopathy in Tinnitus

The contribution of cochlear synaptopathy to tinnitus is still unclear and the subject of ongoing research. Cochlear synaptopathy refers to the loss of synapses between the inner hair cells (IHCs) and the cochlear nerve fibers, which can occur due to external factors such as noise exposure or aging. This condition is sometimes referred to as hidden hearing loss as it cannot be diagnosed through conventional tonal audiometry. Studies have shown a reduced amplitude of wave 1 in the auditory brainstem response (ABR) in people with tinnitus and normal hearing, which has been interpreted as evidence for reduced cochlear nerve output as a result of cochlear synaptopathy. However, this finding has not been consistently replicated, and other factors such as noise exposure may also play a role in tinnitus. Further research is needed to better understand the relationship between cochlear synaptopathy and tinnitus, and to develop improved methods for detecting this condition in humans.

Unraveling the Mechanisms Behind the Persistence of Tinnitus

The maintenance of tinnitus is thought to involve several mechanisms, many of which are associated with hearing loss. Research has shown that there is a strong association between high-pitched tinnitus and high-frequency sensorineural hearing loss (SNHL), suggesting that hearing loss is a main cause of tinnitus (Norena et al., 2002; Martines et al., 2010a,b,c; Sereda et al., 2011).

Studies have shown that the underlying cause of tinnitus may be associated with damage to the sensory cochlear epithelium (Henry et al., 2005), and this damage can result from various kinds of peripheral insults to the auditory system such as cochlear ablation, selective loss of inner hair cells (IHCs) or outer hair cells (OHCs), or mixed or incomplete IHC and OHC injuries. These insults can reduce cochlear output, which may then trigger a cascade of neuromodulatory events ultimately causing hyperactivity in central auditory circuits (central gain).

Reduced cochlear output through hearing loss may modify the gain of central neurons, resulting in increased spontaneous activity, and this increased activity has been proposed to contribute to tinnitus (Parra and Pearlmutter, 2007). The functional aberrations resulting from either the tonotopic over-representation, enhanced synchronicity, or elevated spontaneous firing rates may underlie the induction of tinnitus (Adjamian et al., 2014).

Figure 2 is a representation of the pathophysiology of tinnitus and how it relates to pain and phantom limb perception. The figure explains that damage to the cochlea, such as hair cell loss or synaptic damages, leads to a frequency-specific decrease in output from the cochlear nerve. In response, the central auditory pathway compensates by increasing its activity, leading to increased gain and the perception of a non-existing sound, which is tinnitus.

In addition to the auditory pathway, tinnitus is thought to share non-auditory networks similar to those in chronic pain, such as perception, salience, distress, and memory. These networks can maintain tinnitus in the absence of the initial tinnitus-initiator.

The model also suggests that tinnitus and phantom pain share underlying mechanisms, such as sensory deafferentation resulting in activity in the primary and secondary auditory cortices. This activity becomes a conscious percept when connected to larger brain networks located in the frontal and parietal cortex, such as the self-awareness and salience network. The salience network intersects with the central autonomic control system and is essential for consciously maintaining the phantom perception.

The phantom perception may also be associated with distress and activate non-specific distress networks located in the anterior cingulate cortex, anterior insula, and amygdala. It is also proposed that memory mechanisms may reinforce and maintain awareness of the phantom percept.

Exploring the Central Processes in Tinnitus

Tinnitus has been linked to changes in the central nervous system, in particular, to the phenomenon of homeostatic plasticity. This occurs when auditory neurons in the brain attempt to maintain a neuronal network similar to the one that existed before peripheral damage occurred.

The posteroventral cochlear nucleus (PVCN), the inferior colliculus (IC), the dorsal cochlear nucleus (DCN), and the paraflocculus lobe of the cerebellum (PFL) have been suggested as possible neuronal correlates of tinnitus. There is evidence that elevated responses to sound are common in individuals with tinnitus, particularly in the IC.

Studies in animals have shown increased activity in fusiform neurons of the DCN during noise-induced tinnitus, and this area has been suggested as an important site of maladaptive auditory-somatosensory plasticity. However, a specific drug compound designed to modulate the Kv7.2/3 channel, which has been found to show decreased activity in the DCN after noise-induced tinnitus, has not been found to alleviate tinnitus in humans.

Exploring the Central Processes in Tinnitus

Tinnitus is complex and is still not fully understood. There are several theories on the potential causes of tinnitus, including neuronal hyperactivity in certain regions of the central auditory system and changes in the auditory cortex. One theory suggests that decreased neural input to the cochlear amplifier may lead to increased spontaneous activity and a chain reaction of neuroplastic changes in the afferent auditory relays, eventually leading to tinnitus. Another theory focuses on the brainstem as the place of integration of efferent neuronal drive and afferent tinnitus-related stimuli. Some studies have suggested that the medial olivocochlear bundle may play a role in tinnitus onset, while others have not confirmed this finding.

Electrophysiological measurements have revealed fundamental differences between people with tinnitus and healthy controls, including hyperactivity in the gamma frequency range within the temporal cortex. There have also been observations of aberrant neuronal oscillations in the alpha and gamma frequency range within the frontal cortex. The correlation between tinnitus perception and the frequency band power in EEG and MEG remains unclear, with some studies finding no clear relationship. Acoustic stimulation studies have shown that tinnitus is associated with changes in the delta/theta and gamma frequency bands, although the findings in this area are mixed and not yet fully understood. Overall, while progress has been made in understanding the potential causes of tinnitus, further research is needed to fully understand this complex phenomenon.

Tinnitus complex and multi-faceted involves a range of auditory and non-auditory structures within the brain. In terms of auditory structures, the auditory pathway, including the inner ear and central auditory nuclei, has been shown to be affected in tinnitus, with changes seen in central gain that are related to loss of GABAergic inhibition and decreased activity of specific potassium channels (Kv7.2/3).

Investigating the Non-Auditory Neuronal Networks in the Development of Tinnitus

In addition to the auditory structures, recent research supports the involvement of emotional and cognitive relays of the brain, such as the temporal, parietal, sensorimotor, and limbic cortex, in the pathophysiology of tinnitus. These regions include the medial prefrontal cortex and ventromedial parts of the basal ganglia, dorsal prefrontal regions, the insula, thalamus, anterior and posterior cingulate, amygdala, parahippocampus, hippocampus, and the subcallosal region, including the nucleus accumbens. The precise role of these extra-auditory structures in tinnitus is difficult to determine and may vary depending on the individual tinnitus profile.

There is evidence of a tight interaction between limbic non-auditory and auditory pathways, as well as anatomical and functional abnormalities, in chronic tinnitus, as seen through various neuroimaging techniques. However, not all studies have been able to find significant differences in the connectivity of the auditory network between control and tinnitus groups. It is important to note that the relationship between the psychoacoustic tinnitus characteristics, the degree of tinnitus distress, and underlying neural patterns of activity is not yet scientifically confirmed and requires further study.

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The findings of the study by Daftary et al. (2004) suggest that the reduction in benzodiazepine receptor density in the frontal lobes and the cerebellum of patients with severe chronic tinnitus might play a role in the development and maintenance of tinnitus. The frontal lobes are part of the frontostriatal circuit, which appears to have a central role in the evaluation of sensory stimuli and the management of information flow, as discussed in previous research (Rauschecker et al., 2015). The cerebellum, on the other hand, is known for its role in motor control and coordination, as well as its involvement in cognitive and emotional processes (D'Angelo and De Zeeuw, 2009).

The role of the thalamus, particularly the medial geniculate body (MGB), has also been implicated in the pathology of tinnitus (Caspary and Llano, 2017). The MGB is thought to act as a gatekeeper, regulating the perception of sound on its way to the auditory cortex and the limbic system. Abnormalities in the thalamocortical circuits, as well as in the limbic and auditory cortices, have been suggested to contribute to the development and maintenance of tinnitus (Winer et al., 1999; Rauschecker et al., 2010; Leaver et al., 2011).

Moreover, the potential role of GABA, a neurotransmitter involved in fast synaptic inhibition and persistent tonic inhibition, has been explored in the context of tinnitus. Two opposing hypotheses have been proposed, one suggesting an up-regulation of GABAergic inhibition and the other a suppression of GABAergic inhibition. These observations highlight the complex interplay between different brain regions and their associated neurotransmitter systems in the development and maintenance of tinnitus.

Investigating the Non-Auditory Neuronal Networks in the Development of Tinnitus

These studies show that there is evidence of structural changes in the brain in individuals with tinnitus and/or hearing loss when compared to a control group. However, there is still some variability in the results obtained, which highlights the need for greater standardization in study design and analysis techniques, as well as more precise subtyping of the condition. The left primary auditory cortex and other non-auditory brain structures appear to play a role in the development of tinnitus, but the exact nature of these changes and their relationship to tinnitus and hearing loss is still not fully understood.

In summary, tinnitus is thought to be related to disruptions in neural synchrony between different cortical networks, including the thalamus. The edge effect theory suggests that a steep audiometric edge between normal and impaired hearing may lead to changes in neural synchrony and the development of tinnitus. However, some studies have found tinnitus-related changes in the magnitude of oscillatory power in different frequency bands beyond just the auditory cortex, suggesting a more diffuse network-based interaction between tinnitus perception and memory processes. Another theory is that changes in alpha power in tinnitus patients reflect an enhancement or reduction of the excitability of engaged neuronal networks. Further research is needed to fully understand the pathophysiology of tinnitus and its underlying mechanisms.

Examining the Theoretical Approaches and Models of Tinnitus Pathophysiology

This model suggests that tinnitus may be a result of the auditory system’s predictive coding process, where the auditory subcortex produces spontaneous activity (the tinnitus precursor) which is normally ignored against the prevailing percept of silence. However, in some individuals with tinnitus, the tinnitus precursor becomes more noticeable and the individual perceives a continuous sound even in silence. This model has some similarities with other theories that propose a role for increased neural synchrony in tinnitus development, but the sensory precision tinnitus model also accounts for the graded processing of spontaneous sensory input and the influence of cognitive factors in tinnitus perception.

While this model provides a comprehensive framework to explain tinnitus pathophysiology, it is important to note that this model may not be applicable to all forms of chronic pain, such as central post-stroke pain, and may need to be modified or refined to account for these conditions. The role of predictive coding in tinnitus and chronic pain is an active area of research, and further studies are needed to fully understand the underlying mechanisms of these conditions.

The cognitive-behavioral model of tinnitus proposes that the way a person thinks about and interprets their tinnitus has a significant impact on the level of distress they experience. This model suggests that negative thoughts, beliefs and attitudes about tinnitus can lead to increased anxiety and avoidance behaviors, which can exacerbate the distress associated with tinnitus. The model proposes that by changing the way a person thinks about their tinnitus and by teaching them coping skills, they can reduce the level of distress they experience.

The fear-avoidance model of tinnitus posits that tinnitus-related distress arises from the avoidance of activities and situations that trigger the perception of tinnitus. This model suggests that a person with tinnitus may experience increased anxiety when they encounter sounds that are similar to their tinnitus, leading them to avoid these sounds. Over time, this avoidance can lead to a decrease in the person's quality of life and an increase in their tinnitus-related distress.

Overall, the psychological models of tinnitus provide a framework for understanding the relationship between the cognitive and emotional aspects of tinnitus and their impact on the level of distress experienced by individuals with tinnitus. These models can inform the development of effective treatment strategies, such as cognitive behavioral therapy, that target the psychological components of tinnitus.

Conclusion

In conclusion, tinnitus is a complex and multi-faceted phenomenon that involves both peripheral and central auditory systems, as well as attentional, memory, and emotional systems. Despite the significant advances made in our understanding of tinnitus, much remains to be discovered about its underlying mechanisms. However, the current view of tinnitus is that it is a symptom encompassing a distributed network, and the restoration of cochlear output to the brain may abolish tinnitus. There is a growing body of evidence supporting the use of various therapeutic approaches, including molecular interventions, systemic approaches, and hybrid solutions, for the treatment of tinnitus. However, the therapy of tinnitus will have to be strictly individualized, taking into account the phase of tinnitus pathophysiology, the level of lesion, and the mechanism of tinnitus maintenance. The multidisciplinary approach will be the key to providing optimal care for tinnitus patients, with the goal of improving their subjective well-being.

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LINKS to Youtube videos

THIS VIDEO COMMING SOON

Understanding Somatic Tinnitus: Causes, Symptoms, and Treatments

How to stop Tinnitus FAST -SPOONING METHOD

How to stop Tinnitus FAST -Various Methods Compilation

What Causes Tinnitus And Can It Be Cured

Acknowledgements

https://www.news-medical.net/health/Does-Tinnitus-Affect-the-Brain.aspx#:~:text=Tinnitus%20causes%20changes%20in%20brain,can%20negatively%20impact%20the%20brain.

https://www.frontiersin.org/articles/10.3389/fnins.2018.00866/full

https://www.nidcd.nih.gov/health/tinnitus

original artwork Fernando Vilhena de Mendonça MD,in Figures 2, 3.

Footnotes

^ https://clinicaltrials.gov/ct2/show/NCT02315508?term=QUIET-1&rank=1

^ https://autifony.com/wp-content/uploads/2017/10/AUTIFONY-CLARITY-1-RESULTS-08-Aug-2016-FINAL.pdf

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Keywords: idiopathic, auditory system, pathophysiology, central tinnitus, peripheral tinnitus, causes, maintenance

Citation: Haider HF, Bojić T, Ribeiro SF, Paço J, Hall DA and Szczepek AJ (2018) Pathophysiology of Subjective Tinnitus: Triggers and Maintenance. Front. Neurosci. 12:866. doi: 10.3389/fnins.2018.00866

Received: 08 July 2018; Accepted: 06 November 2018;

Published: 27 November 2018.

Edited by:

Victoria M. Bajo Lorenzana, University of Oxford, United Kingdom

Reviewed by:

Daniel Llano, University of Illinois at Urbana–Champaign, United States

Carine Signoret, Linköping University, Sweden

Copyright © 2018 Haider, Bojić, Ribeiro, Paço, Hall and Szczepek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Haúla Faruk Haider, haula.f.haider@jmellosaude.pt; hfhaider@gmail.com orcid.org/0000-0002-3860-5895 Agnieszka J. Szczepek, Agnes.Szczepek@charite.de orcid.org/0000-0002-9292-6606

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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