[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.

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.

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.

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.

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.

Simulated transient hearing loss improves auditory sensitivity.

Recently, it was proposed that a processing principle called adaptive stochastic resonance plays a major role in the auditory system, and serves to maintain optimal sensitivity even to highly variable sound pressure levels. As a side effect, in case of reduced auditory input, such as permanent hearing loss or frequency specific deprivation, this mechanism may eventually lead to the perception of phantom sounds like tinnitus or the Zwicker tone illusion. Using computational modeling, the biological plausibility of this processing principle was already demonstrated. Here, we provide experimental results that further support the stochastic resonance model of auditory perception. In particular, Mongolian gerbils were exposed to moderate intensity, non-damaging long-term notched noise, which mimics hearing loss for frequencies within the notch. Remarkably, the animals developed significantly increased sensitivity, i.e. improved hearing thresholds, for the frequency centered within the notch, but not for frequencies outside the notch. In addition, most animals treated with the new paradigm showed identical behavioral signs of phantom sound perception (tinnitus) as animals with acoustic trauma induced tinnitus. In contrast, animals treated with broadband noise as a control condition did not show any significant threshold change, nor behavioral signs of phantom sound perception.

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.

Acute and Long-Term Circuit-Level Effects in the Auditory Cortex After Sound Trauma.

Harmful environmental sounds are a prevailing source of chronic hearing impairments, including noise induced hearing loss, hyperacusis, or tinnitus. How these symptoms are related to pathophysiological damage to the sensory receptor epithelia and its effects along the auditory pathway, have been documented in numerous studies. An open question concerns the temporal evolution of maladaptive changes after damage and their manifestation in the balance of thalamocortical and corticocortical input to the auditory cortex (ACx). To address these issues, we investigated the loci of plastic reorganizations across the tonotopic axis of the auditory cortex of male Mongolian gerbils (Meriones unguiculatus) acutely after a sound trauma and after several weeks. We used a residual current-source density analysis to dissociate adaptations of intracolumnar input and horizontally relayed corticocortical input to synaptic populations across cortical layers in ACx. A pure tone-based sound trauma caused acute changes of subcortical inputs and corticocortical inputs at all tonotopic regions, particularly showing a broad reduction of tone-evoked inputs at tonotopic regions around the trauma frequency. At other cortical sites, the overall columnar activity acutely decreased, while relative contributions of lateral corticocortical inputs increased. After 4-6 weeks, cortical activity in response to the altered sensory inputs showed a general increase of local thalamocortical input reaching levels higher than before the trauma. Hence, our results suggest a detailed mechanism for overcompensation of altered frequency input in the auditory cortex that relies on a changing balance of thalamocortical and intracortical input and along the frequency gradient of the cortical tonotopic map.

ß-Secretase BACE1 Is Required for Normal Cochlear Function.

Cleavage of amyloid precursor protein (APP) by ß-secretase BACE1 initiates the production and accumulation of neurotoxic amyloid-ß peptides, which is widely considered an essential pathogenic mechanism in Alzheimer's disease (AD). Here, we report that BACE1 is essential for normal auditory function. Compared with wild-type littermates, BACE1-/- mice of either sex exhibit significant hearing deficits, as indicated by increased thresholds and reduced amplitudes in auditory brainstem responses (ABRs) and decreased distortion product otoacoustic emissions (DPOAEs). Immunohistochemistry revealed aberrant synaptic organization in the cochlea and hypomyelination of auditory nerve fibers as predominant neuropathological substrates of hearing loss in BACE1-/- mice. In particular, we found that fibers of spiral ganglion neurons (SGN) close to the organ of Corti are disorganized and abnormally swollen. BACE1 deficiency also engenders organization defects in the postsynaptic compartment of SGN fibers with ectopic overexpression of PSD95 far outside the synaptic region. During postnatal development, auditory fiber myelination in BACE1-/- mice lags behind dramatically and remains incomplete into adulthood. We relate the marked hypomyelination to the impaired processing of Neuregulin-1 when BACE1 is absent. To determine whether the cochlea of adult wild-type mice is susceptible to AD treatment-like suppression of BACE1, we administered the established BACE1 inhibitor NB-360 for 6 weeks. The drug suppressed BACE1 activity in the brain, but did not impair hearing performance and, upon neuropathological examination, did not produce the characteristic cochlear abnormalities of BACE1-/- mice. Together, these data strongly suggest that the hearing loss of BACE1 knock-out mice represents a developmental phenotype.SIGNIFICANCE STATEMENT Given its crucial role in the pathogenesis of Alzheimer's disease (AD), BACE1 is a prime pharmacological target for AD prevention and therapy. However, the safe and long-term administration of BACE1-inhibitors as envisioned in AD requires a comprehensive understanding of the various physiological functions of BACE1. Here, we report that BACE1 is essential for the processing of auditory signals in the inner ear, as BACE1-deficient mice exhibit significant hearing loss. We relate this deficit to impaired myelination and aberrant synapse formation in the cochlea, which manifest during postnatal development. By contrast, prolonged pharmacological suppression of BACE1 activity in adult wild-type mice did not reproduce the hearing deficit or the cochlear abnormalities of BACE1 null mice.

Open(G)PIAS: An Open-Source Solution for the Construction of a High-Precision Acoustic Startle Response Setup for Tinnitus Screening and Threshold Estimation in Rodents.

The modulation of the acoustic startle reflex (ASR) by a pre-stimulus called pre-pulse inhibition (PPI, for gap of silence pre-stimulus: GPIAS) is a versatile tool to, e.g., estimate hearing thresholds or identify subjective tinnitus percepts in rodents. A proper application of these paradigms depends on a reliable measurement of the ASR amplitudes and an exact stimulus presentation in terms of frequency and intensity. Here, we introduce a novel open-source solution for the construction of a low-cost ASR setup. The complete software for data acquisition and stimulus presentation is written in Python 3.6 and is provided as an Anaconda package. Furthermore, we provide a construction plan for the sensor system based on low-cost hardware components. Exemplary GPIAS data from two animal models (Mus musculus, Meriones unguiculatus) show that the ratio histograms (1-GPIAS) of the gap-pre-stimulus and no pre-stimulus ASR amplitudes can be well described by a log-normal distribution being in good accordance to previous studies with already established setups. Furthermore, it can be shown that the PPI as a function of pre-stimulus intensity (threshold paradigm) can be approximated with a hard-sigmoid function enabling a reproducible sensory threshold estimation. Thus, we show that the open-source solution could help to further establish the ASR method in many laboratories and, thus, facilitate and standardize research in animal models of tinnitus and/or hearing loss.

Objective Estimation of Sensory Thresholds Based on Neurophysiological Parameters.

Reliable determination of sensory thresholds is the holy grail of signal detection theory. However, there exists no assumption-independent gold standard for the estimation of thresholds based on neurophysiological parameters, although a reliable estimation method is crucial for both scientific investigations and clinical diagnosis. Whenever it is impossible to communicate with the subjects, as in studies with animals or neonates, thresholds have to be derived from neural recordings or by indirect behavioral tests. Whenever the threshold is estimated based on such measures, the standard approach until now is the subjective setting-either by eye or by statistical means-of the threshold to the value where at least a "clear" signal is detectable. These measures are highly subjective, strongly depend on the noise, and fluctuate due to the low signal-to-noise ratio near the threshold. Here we show a novel method to reliably estimate physiological thresholds based on neurophysiological parameters. Using surrogate data we demonstrate that fitting the responses to different stimulus intensities with a hard sigmoid function, in combination with subsampling, provides a robust threshold value as well as an accurate uncertainty estimate. This method has no systematic dependence on the noise and does not even require samples in the full dynamic range of the sensory system. We prove that this method is universally applicable to all types of sensory systems, ranging from somatosensory stimulus processing in the cortex to auditory processing in the brain stem.