[The Erlangen model of tinnitus development-New perspective and treatment strategy]. / Erlanger Modell der Tinnitusentstehung ­ Perspektivwechsel und neue Behandlungsstrategie.

BACKGROUND: About one sixth of the population of western industrialized nations suffers from chronic, subjective tinnitus, causing socioeconomic treatment and follow-up costs of almost 22 billion euros per year in Germany alone. According to the prevailing view, tinnitus develops as a consequence of a maladaptive neurophysiological process in the brain triggered by hearing loss. OBJECTIVES: The Erlangen model of tinnitus development presented here is intended to propose a comprehensive neurophysiological explanation for the initial occurrence of the phantom sound after hearing loss. Based on the model, a new treatment strategy will be developed. MATERIALS AND METHODS: The model summarized here is based on various animal and human physiological studies conducted in recent years. RESULTS: The Erlangen model considers subjective tinnitus as a side effect of a physiological mechanism that permanently optimizes information transmission into the auditory system by means of stochastic resonance (SR) even in the healthy auditory system. In fact, hearing-impaired patients with tinnitus hear better on average than those without tinnitus. This unfamiliar perspective on the phantom percept may already help affected patients to cope better with their suffering. In addition, based on the model, low intensity noise tinnitus suppression (LINTS) has been developed as a new, individually adapted treatment strategy for tonal tinnitus and has already been successfully tested in patients. CONCLUSIONS: A possible limiting factor for the model and treatment strategy is the pitch of the tinnitus percept, which may require adjustments to the treatment strategy for frequencies above about 5 kHz.

Predictive coding and stochastic resonance as fundamental principles of auditory phantom perception.

Mechanistic insight is achieved only when experiments are employed to test formal or computational models. Furthermore, in analogy to lesion studies, phantom perception may serve as a vehicle to understand the fundamental processing principles underlying healthy auditory perception. With a special focus on tinnitus-as the prime example of auditory phantom perception-we review recent work at the intersection of artificial intelligence, psychology and neuroscience. In particular, we discuss why everyone with tinnitus suffers from (at least hidden) hearing loss, but not everyone with hearing loss suffers from tinnitus. We argue that intrinsic neural noise is generated and amplified along the auditory pathway as a compensatory mechanism to restore normal hearing based on adaptive stochastic resonance. The neural noise increase can then be misinterpreted as auditory input and perceived as tinnitus. This mechanism can be formalized in the Bayesian brain framework, where the percept (posterior) assimilates a prior prediction (brain's expectations) and likelihood (bottom-up neural signal). A higher mean and lower variance (i.e. enhanced precision) of the likelihood shifts the posterior, evincing a misinterpretation of sensory evidence, which may be further confounded by plastic changes in the brain that underwrite prior predictions. Hence, two fundamental processing principles provide the most explanatory power for the emergence of auditory phantom perceptions: predictive coding as a top-down and adaptive stochastic resonance as a complementary bottom-up mechanism. We conclude that both principles also play a crucial role in healthy auditory perception. Finally, in the context of neuroscience-inspired artificial intelligence, both processing principles may serve to improve contemporary machine learning techniques.

Extracting continuous sleep depth from EEG data without machine learning.

The human sleep-cycle has been divided into discrete sleep stages that can be recognized in electroencephalographic (EEG) and other bio-signals by trained specialists or machine learning systems. It is however unclear whether these human-defined stages can be re-discovered with unsupervised methods of data analysis, using only a minimal amount of generic pre-processing. Based on EEG data, recorded overnight from sleeping human subjects, we investigate the degree of clustering of the sleep stages using the General Discrimination Value as a quantitative measure of class separability. Virtually no clustering is found in the raw data, even after transforming the EEG signals of each 30-s epoch from the time domain into the more informative frequency domain. However, a Principal Component Analysis (PCA) of these epoch-wise frequency spectra reveals that the sleep stages separate significantly better in the low-dimensional sub-space of certain PCA components. In particular the component C1(t) can serve as a robust, continuous 'master variable' that encodes the depth of sleep and therefore correlates strongly with the 'hypnogram', a common plot of the discrete sleep stages over time. Moreover, C1(t) shows persistent trends during extended time periods where the sleep stage is constant, suggesting that sleep may be better understood as a continuum. These intriguing properties of C1(t) are not only relevant for understanding brain dynamics during sleep, but might also be exploited in low-cost single-channel sleep tracking devices for private and clinical use.

Is phase locking crucial to improve hearing thresholds in tinnitus patients?

Temporal processing of auditory data plays a crucial role in our proposed model of tinnitus development through stochastic resonance (SR). The model assumes a physiological mechanism optimizing auditory information transmission (as quantified by autocorrelation [AC] analysis) into the brain by adding the optimal amount of neuronal noise to otherwise subthreshold signals. We hypothesize that this takes place at the second synapse of the auditory pathway in the dorsal cochlear nucleus (DCN). We propose that after hearing loss, this neuronal noise is increased in the affected frequency band to improve hearing thresholds at the cost of upward propagation of this added noise, which finally may be perceived as tinnitus. We already showed the improvement of hearing thresholds in a large population of patients. Until now, we did not investigate the differences in hearing thresholds based on the biological constraints of early auditory temporal processing (phase locking) that is only possible up to frequencies of 5 kHz. In this report, we grouped our patient database (N = 47,986) according to tinnitus pitch (TP) of below (TP<5kHz ) or above (TP>5kHz ) the 5 kHz limit or having no tinnitus (NT) and compared their mean audiograms. We found that TP<5kHz patients showed significantly better hearing thresholds than all other patient groups independent of age. No improvement was seen for TP>5kHz patients who even showed worse thresholds than NT patients for high frequencies. These results are further evidence for our SR model of tinnitus development and the existence of AC analysis at the level of the DCN.

Behavioral Assessment of Zwicker Tone Percepts in Gerbils.

The Zwicker tone illusion - an auditory phantom percept after hearing a notched noise stimulus - can serve as an interesting model for acute tinnitus. Recent mechanistic models suggest that the underlying neural mechanisms of both percepts are similar. To date it is not clear if animals do perceive the Zwicker tone, as up to now no behavioral paradigms are available to objectively assess the presence of this phantom percept. Here we introduce, for the first time, a modified version of the gap pre-pulse inhibition of the acoustic startle reflex (GPIAS) paradigm to test if it is possible to induce a Zwicker tone percept in our rodent model, the Mongolian gerbil. Furthermore, we developed a new aversive conditioning learning paradigm and compare the two approaches. We found a significant increase in the GPIAS effect when presenting a notched noise compared to white noise gap pre-pulse inhibition, which is consistent with the interpretation of a Zwicker tone percept in these animals. In the aversive conditioning learning paradigm, no clear effect could be observed in the discrimination performance of the tested animals. When investigating the first 33% of the correct conditioned responses, an effect of a possible Zwicker tone percept can be seen, i.e. animals show identical behavior as if a pure tone was presented, but the paradigm needs to be further improved. Nevertheless, the results indicate that Mongolian gerbils are able to perceive a Zwicker tone and can serve as a neurophysiological model for human tinnitus generation.

Tinnitus at the Junction of Traditional Medicine and Modern Technology.

The WHO estimated that 430 million people worldwide suffer from moderate-to-severe hearing loss [...].

Classification at the accuracy limit: facing the problem of data ambiguity.

Data classification, the process of analyzing data and organizing it into categories or clusters, is a fundamental computing task of natural and artificial information processing systems. Both supervised classification and unsupervised clustering work best when the input vectors are distributed over the data space in a highly non-uniform way. These tasks become however challenging in weakly structured data sets, where a significant fraction of data points is located in between the regions of high point density. We derive the theoretical limit for classification accuracy that arises from this overlap of data categories. By using a surrogate data generation model with adjustable statistical properties, we show that sufficiently powerful classifiers based on completely different principles, such as perceptrons and Bayesian models, all perform at this universal accuracy limit under ideal training conditions. Remarkably, the accuracy limit is not affected by certain non-linear transformations of the data, even if these transformations are non-reversible and drastically reduce the information content of the input data. We further compare the data embeddings that emerge by supervised and unsupervised training, using the MNIST data set and human EEG recordings during sleep. We find for MNIST that categories are significantly separated not only after supervised training with back-propagation, but also after unsupervised dimensionality reduction. A qualitatively similar cluster enhancement by unsupervised compression is observed for the EEG sleep data, but with a very small overall degree of cluster separation. We conclude that the handwritten letters in MNIST can be considered as 'natural kinds', whereas EEG sleep recordings are a relatively weakly structured data set, so that unsupervised clustering will not necessarily re-cover the human-defined sleep stages.

Systems Medicine Approach for Tinnitus with Comorbid Disorders.

Despite the fact that chronic diseases usually occur together with a spectrum of possible comorbidities that may differ strongly between patients, they are classically still viewed as distinct disease entities and, consequently, are often treated with uniform therapies. Unfortunately, such an approach does not take into account that different combinations of symptoms and comorbidities may result from different pathological (e.g., environmental, genetic, dietary, etc.) factors, which require specific and individualised therapeutic strategies. In this opinion paper, we aim to put forward a more differentiated, systems medicine approach to disease and patient treatment. To elaborate on this concept, we focus on the interplay of tinnitus, depression, and chronic pain. In our view, these conditions can be characterised by a variety of phenotypes composed of variable sets of symptoms and biomarkers, rather than distinct disease entities. The knowledge of the interplay of such symptoms and biomarkers will provide the key to a deeper, mechanistic understanding of disease pathologies. This paves the way for prediction and prevention of disease pathways, including more personalised and effective treatment strategies.

Estimation of Tinnitus-Related Socioeconomic Costs in Germany.

Despite the high prevalence of tinnitus in Germany of nearly 12% of the general population, there have been no systematic studies on the socioeconomic costs for German society caused by tinnitus so far. Here we analyzed data from 258 chronic tinnitus patients-namely tinnitus severity and health utility index (HUI)-and correlated them with their tinnitus-related public health care costs, private expenses, and economic loss due to their tinnitus percept as assessed by questionnaires. We found correlations of the HUI with health care costs and calculated the mean socioeconomic costs per tinnitus patient in Germany. According to our most conservative estimate, these sum up to EUR 4798.91 per year. Of that EUR 2206.95 account for the public health care, EUR 290.45 are carried by the patient privately and the remaining EUR 2301.51 account for economical loss due to sick leave. With a prevalence of 5.5% with at least bothersome tinnitus, this sums up to 21.9 billion Euro per year and with 25.82 sick leave days; tinnitus patients miss work more than double the time of the average German employee (10.9 days). The findings fit within the cost ranges of studies from other European countries and the USA and show that the socioeconomic burden of this disease-like symptom is a global problem. In comparison with the costs of other major chronic diseases in Germany-such as chronic obstructive pulmonary diseases (ca. 16 billion Euro) or diabetes mellitus (ca. 42 billion Euro)-the relevance of the 'symptom' tinnitus for the German social economy becomes even more obvious.

Preventive Effects of Ginkgo-Extract EGb 761® on Noise Trauma-Induced Cochlear Synaptopathy.

Noise trauma-induced loss of ribbon synapses at the inner hair cells (IHC) of the cochlea may lead to hearing loss (HL), resulting in tinnitus. We are convinced that a successful and sustainable therapy of tinnitus has to treat both symptom and cause. One of these causes may be the mentioned loss of ribbon synapses at the IHC of the cochlea. In this study, we investigated the possible preventive and curative effects of the Ginkgo biloba extract EGb 761® on noise-induced synaptopathy, HL, and tinnitus development in Mongolian gerbils (Meriones unguiculatus). To this end, 37 male animals received EGb 761® or placebo orally 3 weeks before (16 animals) or after (21 animals) a monaural acoustic noise trauma (2 kHz, 115 dB SPL, 75 min). Animals' hearing thresholds were determined by auditory brainstem response (ABR) audiometry. A possible tinnitus percept was assessed by the gap prepulse inhibition acoustic startle reflex (GPIAS) response paradigm. Synaptopathy was quantified by cochlear immunofluorescence histology, counting the ribbon synapses of 15 IHCs at 11 different cochlear frequency locations per ear. We found a clear preventive effect of EGb 761® on ribbon synapse numbers with the surprising result of a significant increase in synaptic innervation on the trauma side relative to placebo-treated animals. Consequently, animals treated with EGb 761® before noise trauma did not develop a significant HL and were also less affected by tinnitus compared to placebo-treated animals. On the other hand, we did not see a curative effect (EGb 761® treatment after noise trauma) of the extract on ribbon synapse numbers and, consequently, a significant HL and no difference in tinnitus development compared to the placebo-treated animals. Taken together, EGb 761® prevented noise-induced HL and tinnitus by protecting from noise trauma-induced cochlear ribbon synapse loss; however, in our model, it did not restore lost ribbon synapses.

Circadian Sensitivity of Noise Trauma-Induced Hearing Loss and Tinnitus in Mongolian Gerbils.

Noise-induced hearing loss (HL) has a circadian component: In nocturnal mice, hearing thresholds (HT) have a significantly stronger effect to acoustic trauma when induced during the night compared to rather mild effects on hearing when induced during daytime. Here, we investigate whether such effects are also present in diurnal Mongolian gerbils and determined whether trauma-induced HL correlated with the development of a tinnitus percept in these animals. In particular, we investigated the effects of acoustic trauma (2 kHz, 115 dB SPL, 75 min) on HT and tinnitus development in 34 male gerbils exposed either at 9 AM, 1 PM, 5 PM, or 12 PM. HT was measured by acoustic brainstem response audiometry at defined times 1 day before and 1 week after the trauma. Possible tinnitus percepts were assessed behaviorally by the gap prepulse inhibition of the acoustic startle response at defined times 1 day before and 1 week after the trauma. We found daytime-dependent changes due to trauma in mean HT in a frequency-dependent manner comparable to the results in mice, but the results temporally shifted according to respective activity profiles. Additionally, we found linear correlations of these threshold changes with the strength of the tinnitus percept, with the most prominent correlations in the 5 PM trauma group. Taken together, circadian sensitivity of the HT to noise trauma can also be found in gerbils, and tinnitus strength correlates most strongly with HL only when the trauma is applied at the most sensitive times, which seem to be the evening.

Spectrally Matched Near-Threshold Noise for Subjective Tinnitus Loudness Attenuation Based on Stochastic Resonance.

Recently, we proposed a model of tinnitus development based on a physiological mechanism of permanent optimization of information transfer from the auditory periphery to the central nervous system by means of neuronal stochastic resonance utilizing neuronal noise to be added to the cochlear input, thereby improving hearing thresholds. In this view, tinnitus is a byproduct of this added neuronal activity. Interestingly, in healthy subjects auditory thresholds can also be improved by adding external, near-threshold acoustic noise. Based on these two findings and a pilot study we hypostatized that tinnitus loudness (TL) might be reduced, if the internally generated neuronal noise is substituted by externally provided individually adapted acoustic noise. In the present study, we extended the data base of the first pilot and further optimized our approach using a more fine-grained adaptation of the presented noise to the patients' audiometric data. We presented different spectrally filtered near-threshold noises (-2 dB to +6 dB HL, 2 dB steps) for 40 s each to 24 patients with tonal tinnitus and a hearing deficit not exceeding 40 dB. After each presentation, the effect of the noise on the perceived TL was obtained by patient's response to a 5-scale question. In 21 out of 24 patients (13 women) TL was successfully subjectively attenuated during acoustic near-threshold stimulation using noise spectrally centered half an octave below the individual's tinnitus pitch (TP). Six patients reported complete subjective silencing of their tinnitus percept during stimulation. Acoustic noise is able to reduce TL, but the TP has to be taken into account. Based on our findings, we speculate about a possible future treatment of tinnitus by near-threshold bandpass filtered acoustic noise stimulation, which could be implemented in hearing aids with noise generators.

Microfluidic system for near-patient extraction and detection of miR-122 microRNA biomarker for drug-induced liver injury diagnostics.

Drug-induced liver injury (DILI) results in over 100 000 hospital attendances per year in the UK alone and is a leading cause for the post-marketing withdrawal of new drugs, leading to significant financial losses. MicroRNA-122 (miR-122) has been proposed as a sensitive DILI marker although no commercial applications are available yet. Extracellular blood microRNAs (miRNAs) are promising clinical biomarkers but their measurement at point of care remains time-consuming, technically challenging, and expensive. For circulating miRNA to have an impact on healthcare, a key challenge to overcome is the development of rapid and reliable low-cost sample preparation. There is an acknowledged issue with miRNA stability in the presence of hemolysis and platelet activation, and no solution has been demonstrated for fast and robust extraction at the site of blood draw. Here, we report a novel microfluidic platform for the extraction of circulating miR-122 from blood enabled by a vertical approach and gravity-based bubble mixing. The performance of this disposable cartridge was verified by standard quantitative polymerase chain reaction analysis on extracted miR-122. The cartridge performed equivalently or better than standard bench extraction kits. The extraction cartridge was combined with electrochemical impedance spectroscopy to detect miR-122 as an initial proof-of-concept toward an application in point-of-care detection. This platform enables the standardization of sample preparation and the detection of miRNAs at the point of blood draw and in resource limited settings and could aid the introduction of miRNA-based assays into routine clinical practice.

A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness.

BACKGROUND: The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown. METHODS: Genetic techniques were used in patients with tubular proteinuria and deafness to identify the disease-causing gene. Diagnostic and functional studies were performed in patients and disease models to investigate the pathophysiology. RESULTS: We identified six individuals (5-33 years) with proteinuria and a high-frequency hearing deficit associated with the homozygous missense variant c.1192C>T (p.R398W) in EHD1. Proteinuria (0.7-2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1R398W/R398W knockin mice also showed a high-frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Interestingly, ciliogenesis appeared unaffected in patients and mouse models. In silico structural analysis predicted a destabilizing effect of the R398W variant and possible inference with nucleotide binding leading to impaired EHD1 oligomerization and membrane remodeling ability. CONCLUSIONS: A homozygous missense variant of EHD1 causes a previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and tubular proteinuria. Recessive EHD1 variants should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted.

Sleep as a random walk: a super-statistical analysis of EEG data across sleep stages.

In clinical practice, human sleep is classified into stages, each associated with different levels of muscular activity and marked by characteristic patterns in the EEG signals. It is however unclear whether this subdivision into discrete stages with sharply defined boundaries is truly reflecting the dynamics of human sleep. To address this question, we consider one-channel EEG signals as heterogeneous random walks: stochastic processes controlled by hyper-parameters that are themselves time-dependent. We first demonstrate the heterogeneity of the random process by showing that each sleep stage has a characteristic distribution and temporal correlation function of the raw EEG signals. Next, we perform a super-statistical analysis by computing hyper-parameters, such as the standard deviation, kurtosis, and skewness of the raw signal distributions, within subsequent 30-second epochs. It turns out that also the hyper-parameters have characteristic, sleep-stage-dependent distributions, which can be exploited for a simple Bayesian sleep stage detection. Moreover, we find that the hyper-parameters are not piece-wise constant, as the traditional hypnograms would suggest, but show rising or falling trends within and across sleep stages, pointing to an underlying continuous rather than sub-divided process that controls human sleep. Based on the hyper-parameters, we finally perform a pairwise similarity analysis between the different sleep stages, using a quantitative measure for the separability of data clusters in multi-dimensional spaces.

Too Blind to See the Elephant? Why Neuroscientists Ought to Be Interested in Tinnitus.

A curative therapy for tinnitus currently does not exist. One may actually exist but cannot currently be causally linked to tinnitus due to the lack of consistency of concepts about the neural correlate of tinnitus. Depending on predictions, these concepts would require either a suppression or enhancement of brain activity or an increase in inhibition or disinhibition. Although procedures with a potential to silence tinnitus may exist, the lack of rationale for their curative success hampers an optimization of therapeutic protocols. We discuss here six candidate contributors to tinnitus that have been suggested by a variety of scientific experts in the field and that were addressed in a virtual panel discussion at the ARO round table in February 2021. In this discussion, several potential tinnitus contributors were considered: (i) inhibitory circuits, (ii) attention, (iii) stress, (iv) unidentified sub-entities, (v) maladaptive information transmission, and (vi) minor cochlear deafferentation. Finally, (vii) some potential therapeutic approaches were discussed. The results of this discussion is reflected here in view of potential blind spots that may still remain and that have been ignored in most tinnitus literature. We strongly suggest to consider the high impact of connecting the controversial findings to unravel the whole complexity of the tinnitus phenomenon; an essential prerequisite for establishing suitable therapeutic approaches.

Pharmacologic treatments in preclinical tinnitus models with special focus on Ginkgo biloba leaf extract EGb 761®.

Tinnitus is defined as the perception of sound in the absence of external acoustic stimuli. Frequent comorbidities or associated factors are depression, anxiety, concentration problems, insomnia, resignation, helplessness, headache, bruxism, or social isolation, just to name a few. Although many therapeutic approaches have already been tested with varying success, there still is no cure available for tinnitus. The search for an effective treatment has been hampered by the fact that the mechanisms of tinnitus development are still not fully understood, although several models are available and discussed in this review. Our review will give a brief overview about preclinical models, presenting the heterogeneity of tinnitus sub-types depending on the different inner ear and brain structures involved in tinnitus etiology and pathogenesis. Based on these models we introduce the different target structures and transmitter systems implicated in tinnitus development and provide an extensive overview on preclinical drug-based therapeutic approaches that have been explored in various animal models. As the special extract from Ginkgo biloba leaves EGb 761® has been the most widely tested drug in both non-clinical tinnitus models as well as in clinical trials, a special focus will be given to EGb 761®. The efficacy of terpene lactones, flavone glycosides and proanthocyanidines with their distinct contribution to the overall efficacy profile of the multi-constituent drug EGb 761® will be discussed.

Salicylate-Induced Changes in Hearing Thresholds in Mongolian Gerbils Are Correlated With Tinnitus Frequency but Not With Tinnitus Strength.

Tinnitus is an auditory phantom percept without external sound sources. Despite the high prevalence and tinnitus-associated distress of affected patients, the pathophysiology of tinnitus remains largely unknown, making prevention and treatments difficult to develop. In order to elucidate the pathophysiology of tinnitus, animal models are used where tinnitus is induced either permanently by noise trauma or transiently by the application of salicylate. In a model of trauma-induced tinnitus, we have suggested a central origin of tinnitus-related development of neuronal hyperactivity based on stochastic resonance (SR). SR refers to the physiological phenomenon that weak subthreshold signals for given sensors (or synapses) can still be detected and transmitted if appropriate noise is added to the input of the sensor. The main objective of this study was to characterize the neurophysiological and behavioral effects during salicylate-induced tinnitus and compare these to the conditions within the trauma model. Our data show, in line with the pharmacokinetics, that hearing thresholds generally increase 2 h after salicylate injections. This increase was significantly stronger within the region of best hearing compared to other frequencies. Furthermore, animals showed behavioral signs of tinnitus during that time window and frequency range as assessed by gap prepulse inhibition of the acoustic startle reflex (GPIAS). In contrast to animals with noise trauma-induced tinnitus, salicylate-induced tinnitus animals showed no correlation between hearing thresholds and behavioral signs of tinnitus, indicating that the development of tinnitus after salicylate injection is not based on SR as proposed for the trauma model. In other words, salicylate-induced tinnitus and noise trauma-induced tinnitus are not based on the same neurophysiological mechanism.

Tinnitus development is associated with synaptopathy of inner hair cells in Mongolian gerbils.

Human hearing loss (HL) is often accompanied by comorbidities like tinnitus, which is affecting up to 15% of the adult population. Rodent animal studies could show that tinnitus may not only be a result of apparent HL due to cochlear hair cell damage but can also be a consequence of synaptopathy at the inner hair cells (IHCs) already induced by moderate sound traumata. Here, we investigate synaptopathy previously shown in mice in our animal model, the Mongolian gerbil, and relate it to behavioral signs of tinnitus. Tinnitus was induced by a mild monaural acoustic trauma leading to monaural noise induced HL in the animals, quantified by auditory brainstem response (ABR) audiometry. Behavioral signs of tinnitus percepts were detected by measurement of prepulse inhibition of the acoustic startle response in a gap-noise paradigm. Fourteen days after trauma, the cochleae of both ears were isolated, and IHC synapses were counted within several spectral regions of the cochlea. Behavioral signs of tinnitus were only found in animals with IHC synaptopathy, independent of type of HL. On the other hand, animals with apparent HL but without behavioral signs of tinnitus showed a reduction in amplitudes of ABR waves I&II but no significant changes in the number of synapses at the IHC. We conclude-in line with the literature-that HL is caused by damage to the IHC or by other reasons but that the development of tinnitus, at least in our animal model, is closely linked to synaptopathy at the IHC.

The stochastic resonance model of auditory perception: A unified explanation of tinnitus development, Zwicker tone illusion, and residual inhibition.

Stochastic resonance (SR) has been proposed to play a major role in auditory perception, and to maintain optimal information transmission from the cochlea to the auditory system. By this, the auditory system could adapt to changes of the auditory input at second or even sub-second timescales. In case of reduced auditory input, somatosensory projections to the dorsal cochlear nucleus would be disinhibited in order to improve hearing thresholds by means of SR. As a side effect, the increased somatosensory input corresponding to the observed tinnitus-associated neuronal hyperactivity is then perceived as tinnitus. In addition, the model can also explain transient phantom tone perceptions occurring after ear plugging, or the Zwicker tone illusion. Vice versa, the model predicts that via stimulation with acoustic noise, SR would not be needed to optimize information transmission, and hence somatosensory noise would be tuned down, resulting in a transient vanishing of tinnitus, an effect referred to as residual inhibition.