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Tinnitus: animal models and findings in humans
Abstract and Figures
Chronic tinnitus (ringing of the ears) is a medically untreatable condition that reduces quality of life for millions of individuals worldwide. Most cases are associated with hearing loss that may be detected by the audiogram or by more sensitive measures. Converging evidence from animal models and studies of human tinnitus sufferers indicates that, while cochlear damage is a trigger, most cases of tinnitus are not generated by irritative processes persisting in the cochlea but by changes that take place in central auditory pathways when auditory neurons lose their input from the ear. Forms of neural plasticity underlie these neural changes, which include increased spontaneous activity and neural gain in deafferented central auditory structures, increased synchronous activity in these structures, alterations in the tonotopic organization of auditory cortex, and changes in network behavior in nonauditory brain regions detected by functional imaging of individuals with tinnitus and corroborated by animal investigations. Research on the molecular mechanisms that underlie neural changes in tinnitus is in its infancy and represents a frontier for investigation.
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... Despite intensive research, its mechanisms remain only incompletely understood and there is essentially no effective treatment (Shore et al., 2016;Henton and Tzounopoulos, 2021). Tinnitus is usually triggered by hearing loss and very often by traumatic exposure to noise (Eggermont and Roberts, 2015). According to the generally accepted idea, cochlear damage caused by acoustic trauma leads to maladaptive changes in the auditory and non-auditory circuits and to the development of tinnitus (Roberts et al., 2010;Henry et al., 2014;Henton and Tzounopoulos, 2021). ...
... For this purpose, we used the GPIAS paradigm (Turner et al., 2006), as have previous similar studies (Ahlf et al., 2012;Li et al., 2015;Miyakawa et al., 2019). This test has its limits and depends on parameters such as the magnitude of ASR and the severity of hearing loss after noise exposure (reviewed in Eggermont and Roberts, 2015;Galazyuk and Hebert, 2015;Shore et al., 2016;Henton and Tzounopoulos, 2021). Our data show that +T and −T mice had similar pre-exposure GPIAS values and that for all mice in this study, these values were not significantly correlated before and after exposure. ...
Noise-induced tinnitus is generally associated with hearing impairment caused by traumatic acoustic overexposure. Previous studies in laboratory animals and human subjects, however, have observed differences in tinnitus susceptibility, even among individuals with similar hearing loss. The mechanisms underlying increased sensitivity or, conversely, resistance to tinnitus are still incompletely understood. Here, we used behavioral tests and ABR audiometry to compare the sound-evoked responses of mice that differed in the presence of noise-induced tinnitus. The aim was to find a specific pre-exposure neurophysiological marker that would predict the development of tinnitus after acoustic trauma. Noise-exposed mice were screened for tinnitus-like behavior with the GPIAS paradigm and subsequently divided into tinnitus (+T) and non-tinnitus (−T) groups. Both groups showed hearing loss after exposure, manifested by elevated audiometric thresholds along with reduced amplitudes and prolonged latencies of ABR waves. Prior to exposure, except for a slightly increased slope of growth function for ABR amplitudes in +T mice, the two groups did not show significant audiometric differences. Behavioral measures, such as the magnitude of the acoustic startle response and its inhibition by gap pre-pulse, were also similar before exposure in both groups. However, +T mice showed significantly increased suppression of the acoustic startle response in the presence of background noise of moderate intensity. Thus, increased modulation of startle by background sounds may represent a behavioral correlate of susceptibility to noise-induced tinnitus, and its measurement may form the basis of a simple non-invasive method for predicting tinnitus development in laboratory rodents.
... Tinnitus itself is most probably induced by the HL [8] but can be modulated by stress or other factors [14] and in turn alter the hearing thresholds [15]. The neuronal basis of tinnitus development and chroni cation is still under debate [15,49] but can be divided into two different stages: the initial and continuing bottom-up changes along the auditory pathway related to the HL and the secondary top-down in uences from higher cortical areas and / or the limbic system. Both stages can interact over time with each other. ...
Tinnitus is a symptom often associated with hearing loss (HL) and is in many cases more burdening to the individual than the HL itself. Many approaches have been made to explain the development and chronification of the phantom percept as well as different treatment strategies to lower the tinnitus related burden. In many studies, the variance of the HL data is high and therefore the interpretation of specific data might be difficult. With this retrospective study, we attempt to explain a part of this variance by investigating specifically the effects of non-auditory comorbidity categories on pure-tone audiometric data in a tinnitus patient collective that was homogeneous with respect to auditory comorbidities. We found age dependent as well as number of non-auditory comorbidity (e.g. diabetes mellitus) dependent differences in the mean HL of the tinnitus patients as well as differences in the peak HL frequency relative to the tinnitus frequency. The analysis of the age dependent HL within the different non-auditory comorbidities revealed specific – partially opposed – effects of endocrine, circulatory, muscle-skeletal and digestive disease categories on the hearing thresholds of tinnitus patients. Taken together we argue that in future tinnitus (and non-tinnitus) patient studies also non-auditory comorbidities should be taken into account as possible covariables that might explain the variance found in the auditory threshold development of these patients.
... Bilateral activations within the occipital lobes further accentuate the multi-dimensional neural backdrop of tinnitus. The prominence of STG and MTG in our observations resonates with the extant literature, delineating their cardinal roles in auditory perception and intricate auditory processing (Eggermont & Roberts, 2015). Their pronounced presence in our ALFF assessment hints at potential disruptions in intrinsic neural oscillations, suggesting aberrant auditory pathways or distorted auditory representations that might be emblematic of tinnitus (Weisz et al., 2005). ...
... Bilateral activations within the occipital lobes further accentuate the multi-dimensional neural backdrop of tinnitus. The prominence of STG and MTG in our observations resonates with the extant literature, delineating their cardinal roles in auditory perception and intricate auditory processing (Eggermont & Roberts, 2015). Their pronounced presence in our ALFF assessment hints at potential disruptions in intrinsic neural oscillations, suggesting aberrant auditory pathways or distorted auditory representations that might be emblematic of tinnitus (Weisz et al., 2005). ...
The origin of tinnitus remains a topic of discussion; however, numerous resting-state functional magnetic resonance imaging (rsfMRI) studies interpret it as a disruption in neural functional connectivity. Yet, there’s notable inconsistency in the resting-state data across these studies. To shed light on this discrepancy, we conducted a meta-analysis of extant rsfMRI studies, aiming to identify potential regions that consistently signify core abnormalities in individuals with tinnitus. Methods: A systematic search on MEDLINE/PubMed, Google Scholar, and Scopus databases was performed to identify rsfMRI studies on tinnitus published up to October 2022. Coordinates related to the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) brain maps that showed significant differences between tinnitus patients and controls were extracted. Meta-analysis was performed using the activation likelihood estimation method. Data were included from 17 rsfMRI studies that reported a total of 63 distinct foci in ALFF and 46 foci in ReHo. Results: Our meta-analysis revealed several regions where tinnitus patients demonstrated increased ALFF and ReHO values, both individually and collectively, when compared to control subjects. These regions encompassed the insula, middle temporal gyrus, and inferior frontal gyrus on both sides. Additionally, increased activity was also noted in the cerebellum posterior lobe bilaterally and the right superior frontal gyrus. Conclusions: This meta-analysis demonstrates a unique pattern of resting-state brain abnormalities involving both the auditory and non-auditory brain regions as neuroimaging markers, which helps understand the neuro-pathophysiological mechanisms of tinnitus.
... www.nature.com/scientificreports/ trauma, thereby surely leading to severe hearing deficits [16][17][18] , but also studies in humans with the participants often representing various levels of hearing loss [10][11][12][13][14][15] . At the molecular level, tinnitus is described in the framework of disrupted excitation-inhibition homeostasis, mainly mediated by glutamate (Glu) and gamma-aminobutyric acid (GABA), at several levels of the auditory pathway, including in the primary auditory cortex 4,19 . ...
Previous studies indicate changes in neurotransmission along the auditory pathway in subjective tinnitus. Most authors, however, investigated brain regions including the primary auditory cortex, whose physiology can be affected by concurrent hearing deficits. In the present MR spectroscopy study we assumed increased levels of glutamate and glutamine (Glx), and other Central Nervous System metabolites in the temporal lobe outside the primary auditory cortex, in a region involved in conscious auditory perception and memory. We studied 52 participants with unilateral (n = 24) and bilateral (n = 28) tinnitus, and a control group without tinnitus (n = 25), all with no severe hearing losses and a similar hearing profile. None of the metabolite levels in the temporal regions of interest were found related to tinnitus status or laterality. Unexpectedly, we found a tendency of increased concentration of Glx in the control left medial frontal region in bilateral vs unilateral tinnitus. Slightly elevated depressive and anxiety symptoms were also shown in participants with tinnitus, as compared to healthy individuals, with the bilateral tinnitus group marginally more affected. We discuss no apparent effect in the temporal lobes, as well as the role of frontal brain areas, with respect to hearing loss, attention and psychological well-being in chronic tinnitus. We furthermore elaborate on the design-related and technical obstacles of MR spectroscopy.
Purpose
The goal of this study was to observe sensory gating–related networks underlying cortical auditory evoked potential (CAEP) peak components in individuals with and without minimal tinnitus, as measured using the Tinnitus Handicap Inventory (THI). This analysis was performed on previously published sensory gating responses in normal-hearing adults with and without minimal tinnitus.
Method
Independent component analysis was performed for each individual CAEP gating component (Pa, P50, N1, and P2). Significant components were retained for source localization analyses within the following groups: no tinnitus, tinnitus with a THI score ≤ 6, and tinnitus with a THI score > 6. Brain source localization was performed on the gating difference wave for each component using standardized low-resolution brain electromagnetic tomography.
Results
Gating-related networks were identified within each group. Different regional sources were observed between groups, with parietal sources underlying the Pa and P50 components as tinnitus severity increased. A larger prefrontal regional activation was also shown for the N1 gating component as tinnitus severity increased. These results expand upon the functional gating responses via CAEP waveforms in a previously published study.
Conclusions
The auditory gating response, as measured via CAEPs, has previously been shown to significantly correlate with an increase in tinnitus severity in adults with normal hearing. The corresponding changes in the gating response appear to be supported by different cortical regions in those without tinnitus, those with a THI score ≤ 6, and those with a THI score > 6. Next, functional differences between localized cortical regions should be tested.
Tinnitus is a widespread public health issue that imposes a significant social burden. The occurrence and maintenance of tinnitus have been shown to be associated with abnormal neuronal activity in the auditory pathway. Based on this view, neurobiological and pharmacological developments in tinnitus focus on ion channels and synaptic neurotransmitter receptors in neurons in the auditory pathway. With major breakthroughs in the pathophysiology and research methodology of tinnitus in recent years, the role of the largest family of ion channels, potassium ion channels, in modulating the excitability of neurons involved in tinnitus has been increasingly demonstrated. More and more potassium channels involved in the neural mechanism of tinnitus have been discovered, and corresponding drugs have been developed. In this article, we review animal (mouse, rat, hamster, and guinea‐pig), human, and genetic studies on the different potassium channels involved in tinnitus, analyze the limitations of current clinical research on potassium channels, and propose future prospects. The aim of this review is to promote the understanding of the role of potassium ion channels in tinnitus and to advance the development of drugs targeting potassium ion channels for tinnitus.
Tinnitus, reduced sound-level tolerance, and difficulties hearing in noisy environments are the most common complaints associated with sensorineural hearing loss in adult populations. This study aims to clarify if cochlear neural degeneration estimated in a large pool of participants with normal audiograms is associated with self-report of tinnitus using a test battery probing the different stages of the auditory processing from hair cell responses to the auditory reflexes of the brainstem. Self-report of chronic tinnitus was significantly associated with (1) reduced cochlear nerve responses, (2) weaker middle-ear muscle reflexes, (3) stronger medial olivocochlear efferent reflexes and (4) hyperactivity in the central auditory pathways. These results support the model of tinnitus generation whereby decreased neural activity from a damaged cochlea can elicit hyperactivity from decreased inhibition in the central nervous system.
Tinnitus has been widely investigated in order to draw conclusions about the underlying causes and altered neural activity in various brain regions. Existing studies have based their work on different tinnitus frameworks, ranging from a more local perspective on the auditory cortex to the inclusion of broader networks and various approaches towards tinnitus perception and distress. Magnetoencephalography (MEG) provides a powerful tool for efficiently investigating tinnitus and aberrant neural activity both spatially and temporally. However, results are inconclusive, and studies are rarely mapped to theoretical frameworks. The purpose of this review was to firstly introduce MEG to interested researchers and secondly provide a synopsis of the current state. We divided recent tinnitus research in MEG into study designs using resting state measurements and studies implementing tone stimulation paradigms. The studies were categorized based on their theoretical foundation, and we outlined shortcomings as well as inconsistencies within the different approaches. Finally, we provided future perspectives on how to benefit more efficiently from the enormous potential of MEG. We suggested novel approaches from a theoretical, conceptual, and methodological point of view to allow future research to obtain a more comprehensive understanding of tinnitus and its underlying processes.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10162-023-00916-z.
To measure tinnitus induced by sodium salicylate injections, 84 rats were used in a conditioned suppression paradigm. In Exp 1, Ss were trained with a conditioned stimulus/stimuli (CS) consisting of the offset of a continuous background noise. One group began salicylate injections before Pavlovian training, a 2nd group started injections after training, and a control group received daily saline injections. Resistance to extinction was profound when injections started before training but minimal when initiated after training, suggesting that salicylate-induced effects acquired differential conditioned value. In Exp 2, salicylate treatments were mimicked by substituting a 7 kHz tone in place of respective injections, resulting in effects equivalent to salicylate-induced behavior. A 3rd experiment included a 3 kHz CS, and again replicated the salicylate findings. In Exp 4, we decreased the motivational level, and the sequential relation between salicylate-induced effects and suppression training was retained. Findings support the demonstration of phantom auditory sensations in animals. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Tinnitus refers to the perception of sound in the absence of external sound. Although this can include the perception of internal sounds, it is most often used to designate the perception of sound in the complete absence of acoustic stimulation, which is the way it is used here (e.g., McFadden, 1982; Penner & Jastreboff, 1996). Of the various causes of tinnitus, the best known are exposure to loud sound and the ingestion of large doses of ototoxic drugs, such as salicylate, which is the active ingredient of aspirin, or quinine, which is a former treatment for malaria and a current flavor component of tonic water. Interest in tinnitus has increased in recent years, aimed primarily at finding a treatment, but understanding this disorder may also give some insight into the neurological basis of the perception of sound. Because carefully controlled studies of neurological disorders are best conducted with animals, this has created a need for a way to determine if an animal has tinnitus.
Central auditory circuits are influenced by the somatosensory system, a relationship that may underlie tinnitus generation. In the guinea pig dorsal cochlear nucleus (DCN), pairing spinal trigeminal nucleus (Sp5) stimulation with tones at specific intervals and orders facilitated or suppressed subsequent tone-evoked neural responses, reflecting spike-timing-dependent plasticity (STDP). Furthermore, after noise-induced tinnitus, bimodal responses in DCN were shifted from Hebbian to anti-Hebbian timing rules with less discrete temporal windows, suggesting a role for bimodal plasticity in tinnitus. Here, we aimed to determine if multisensory STDP principles like those in DCN also exist in primary auditory cortex (A1), and whether they change following noise-induced tinnitus. Tone-evoked and spontaneous neural responses were recorded before, and 15 min after bimodal stimulation in which the intervals and orders of auditory-somatosensory stimuli were randomized. Tone-evoked and spontaneous firing rates were influenced by the interval and order of the bimodal stimuli and in sham-controls Hebbian-like timing rules predominated as was seen in DCN. In noise-exposed animals with and without tinnitus, timing rules shifted away from those found in sham-controls to more anti-Hebbian rules. Only those animals with evidence of tinnitus showed increased spontaneous firing rates, a purported neurophysiologic correlate of tinnitus in A1. Together, these findings suggest that bimodal plasticity is also evident in A1 following noise damage and may have implications for tinnitus generation and therapeutic intervention across the central auditory circuit.
Copyright © 2015, Journal of Neurophysiology.
To test the “tinnitus gap-filling” hypothesis in an animal psychoacoustic paradigm, rats were tested using a go/no-go operant gap detection task in which silent intervals of various durations were embedded within a continuous noise. Gap detection thresholds were measured before and after treatment with a dose of sodium salicylate (200 mg/kg) that reliably induces tinnitus in rats. Noise-burst detection thresholds were also measured to document the amount of hearing loss and aid in interpreting the gap detection results. As in the previous human psychophysical experiments, salicylate had little or no effect on gap thresholds measured in broadband noise presented at high-stimulus levels (30–60 dB SPL); gap detection thresholds were always 10 ms or less. Salicylate also did not affect gap thresholds presented in narrowband noise at 60 dB SPL. Therefore, rats treated with a dose of salicylate that reliably induces tinnitus have no difficulty detecting silent gaps as long as the noise in which they are embedded is clearly audible.
In this paper, we review studies that have investigated brain morphology in chronic tinnitus in order to better understand the underlying pathophysiology of the disorder. Current consensus is that tinnitus is a disorder involving a distributed network of peripheral and central pathways in the nervous system. However, the precise mechanism remains elusive and it is unclear which structures are involved. Given that brain structure and function are highly related, identification of anatomical differences may shed light upon the mechanism of tinnitus generation and maintenance. We discuss anatomical changes in the auditory cortex, the limbic system, and prefrontal cortex, among others. Specifically, we discuss the gating mechanism of tinnitus and evaluate the evidence in support of the model from studies of brain anatomy. Although individual studies claim significant effects related to tinnitus, outcomes are divergent and even contradictory across studies. Moreover, results are often confounded by the presence of hearing loss. We conclude that, at present, the overall evidence for structural abnormalities specifically related to tinnitus is poor. As this area of research is expanding, we identify some key considerations for research design and propose strategies for future research.
Tinnitus is an auditory sensation (ringing of the ears) experienced when no external sound is present. Tinnitus is commonly divided into objective and subjective tinnitus. This article considers subjective tinnitus, which is a phantom sound sensation often accompanying hearing loss and head and neck injuries, or manifesting itself as a hypersensitivity to various drugs. Tinnitus sensations associated with hearing loss are nearly always localized towards the affected ear. This article discusses the issue if tinnitus is in the ear or in the brain. Tinnitus-inducing agents in humans have been listed on the basis of epidemiological and clinical studies. This suggests that most often tinnitus is related to hearing loss and potentially exacerbated by aging. There is a large body of literature, mainly originating from studies of the visual cortex, that suggests a role of neural synchrony in perceptual binding.
This book examines tinnitus from the viewpoint of a neuroscientist with a long background in translational research. Therefore the book focuses on the understanding of the mechanisms that underlie tinnitus and is based on data-driven approaches to characterize its properties in humans and in animal models. It is hoped that a better and coherent understanding of the findings from the various neuroscience methods, ranging from brain imaging, electrophysiology, and quantifying the subjective aspects of tinnitus, to molecular biology and genetic aspects, will lead to more and better science driven approaches to alleviate tinnitus and ultimately produce a cure. For the backbone for the book three well-researched animal models of tinnitus, the salicylate, noise trauma, and somatic models, and in addition, the hypersynchrony model that is aimed at the integration of these three models were used. The reasons to use these models are found in human research, which is extensively described. An extensive discussion of the pros and cons of behavioral animal models that are employed to decide whether an animal has tinnitus is presented. The book advocates the role that modified brain networks may play in generating and maintaining tinnitus. This is the most speculative part of the book. Epidemiology and etiology, and evidence-based management of tinnitus have their own place at the beginning and end of this book.