Roland Schaette

Tinnitus with a Normal Audiogram: Physiological Evidence for Hidden Hearing Loss and Computational Model

Ever since Pliny the Elder coined the term tinnitus, the perception of sound in the absence of an external sound source has remained enigmatic. Traditional theories assume that tinnitus is triggered by cochlear damage, but many tinnitus patients present with a normal audiogram, i.e., with no direct signs of cochlear damage. Here, we report that in human subjects with tinnitus and a normal audiogram, auditory brainstem responses show a significantly reduced amplitude of the wave I potential (generated by primary auditory nerve fibers) but normal amplitudes of the more centrally generated wave V. This provides direct physiological evidence of “hidden hearing loss” that manifests as reduced neural output from the cochlea, and consequent renormalization of neuronal response magnitude within the brainstem. Employing an established computational model, we demonstrate how tinnitus could arise from a homeostatic response of neurons in the central auditory system to reduced auditory nerve input in the absence of elevated hearing thresholds.

Development of tinnitus-related neuronal hyperactivity through homeostatic plasticity after hearing loss: a computational model

Tinnitus, the perception of a sound in the absence of acoustic stimulation, is often associated with hearing loss. Animal studies indicate that hearing loss through cochlear damage can lead to behavioral signs of tinnitus that are correlated with pathologically increased spontaneous firing rates, or hyperactivity, of neurons in the auditory pathway. Mechanisms that lead to the development of this hyperactivity, however, have remained unclear. We address this question by using a computational model of auditory nerve fibers and downstream auditory neurons. The key idea is that mean firing rates of these neurons are stabilized through a homeostatic plasticity mechanism. This homeostatic compensation can give rise to hyperactivity in the model neurons if the healthy ratio between mean and spontaneous firing rate of the auditory nerve is decreased, for example through a loss of outer hair cells or damage to hair cell stereocilia. Homeostasis can also amplify non‐auditory inputs, which then contribute to hyperactivity. Our computational model predicts how appropriate additional acoustic stimulation can reverse the development of such hyperactivity, which could provide a new basis for treatment strategies.

Course of hearing loss and occurrence of tinnitus

Chronic tinnitus is often accompanied by a hearing impairment, but it is still unknown whether hearing loss can actually cause tinnitus. The association between the pitch of the tinnitus sensation and the audiogram edge in patients with high-frequency hearing loss suggests a functional relation, but a large fraction of patients with hearing loss does not present symptoms of tinnitus. We therefore, investigated how the occurrence of tinnitus is related to the shape of the audiogram. We analyzed a sample where all patients had noise-induced hearing loss, containing 30 patients without tinnitus, 24 patients with tone-like tinnitus, and 17 patients with noise-like tinnitus. All patients had moderate to severe high-frequency hearing loss, and only minor to moderate hearing loss at low frequencies. We found that tinnitus patients had less overall hearing loss than patients without tinnitus. Moreover, the maximum steepness of the audiogram was higher in patients with tinnitus (-52.9+/-1.9 dB/octave) compared to patients without tinnitus (-43.1+/-2.4 dB/octave). Differences in overall hearing loss and maximum steepness between tone-like and noise-like tinnitus were not significant. For tone-like tinnitus, there was a clear association between the tinnitus pitch and the edge of the audiogram, with tinnitus pitch being on average 1.48+/-0.12 octaves above the audiogram edge frequency, and 0.81+/-0.1 octaves above the frequency with the steepest slope. Our results suggest that the occurrence of tinnitus is promoted by a steep audiogram slope. A steep slope leads to abrupt discontinuities in the activity along the tonotopic axis of the auditory system, which could be misinterpreted as sound.

Acoustic stimulation treatments against tinnitus could be most effective when tinnitus pitch is within the stimulated frequency range.

Acoustic stimulation with hearing aids or noise devices is frequently used in tinnitus therapy. However, such behind-the-ear devices are limited in their high-frequency output with an upper cut-off frequency of approximately 5-6 kHz. Theoretical modeling suggests that acoustic stimulation treatments with these devices might be most effective when the tinnitus pitch is within the stimulated frequency range. To test this hypothesis, we conducted a pilot study with 15 subjects with chronic tinnitus. Eleven subjects received hearing aids and four subjects noise devices. Perceived tinnitus loudness was measured using a visual analog scale, and tinnitus-related distress was assessed using the Tinnitus Questionnaire. After six months of device usage, reductions of perceived tinnitus loudness were seen only in subjects with a tinnitus pitch of less than 6 kHz. When subjects were grouped by tinnitus pitch, the group of patients with a tinnitus pitch of less than 6 kHz (n = 10 subjects) showed a significant reduction in perceived tinnitus loudness (from 73.4 +/- 6.1 before to 56.4 +/- 7.4 after treatment, p = 0.012), whereas in subjects with a tinnitus pitch of 6 kHz or more (n = 5 subjects) tinnitus loudness was slightly increased after six months of treatment (65.0 +/- 4.7 before and 70.6 +/- 5.9 after treatment), but the increase was not significant (p = 0.063). Likewise, tinnitus-related distress was significantly decreased in the low-pitch group (from 31.6 +/- 4.3 to 20.9 +/- 4.8, p = 0.0059), but not in the group with high-pitched tinnitus (30.2 +/- 3.3 before and 30.0 +/- 5.1 after treatment, p = 1). Overall, reductions in tinnitus-related distress in our study were less pronounced than those reported for more comprehensive treatments. However, the differences we observed between the low- and the high-pitch group show that tinnitus pitch might influence the outcome of acoustic stimulation treatments when devices with a limited frequency range are used.

Reversible Induction of Phantom Auditory Sensations through Simulated Unilateral Hearing Loss

Tinnitus, a phantom auditory sensation, is associated with hearing loss in most cases, but it is unclear if hearing loss causes tinnitus. Phantom auditory sensations can be induced in normal hearing listeners when they experience severe auditory deprivation such as confinement in an anechoic chamber, which can be regarded as somewhat analogous to a profound bilateral hearing loss. As this condition is relatively uncommon among tinnitus patients, induction of phantom sounds by a lesser degree of auditory deprivation could advance our understanding of the mechanisms of tinnitus. In this study, we therefore investigated the reporting of phantom sounds after continuous use of an earplug. 18 healthy volunteers with normal hearing wore a silicone earplug continuously in one ear for 7 days. The attenuation provided by the earplugs simulated a mild high-frequency hearing loss, mean attenuation increased from <10 dB at 0.25 kHz to >30 dB at 3 and 4 kHz. 14 out of 18 participants reported phantom sounds during earplug use. 11 participants presented with stable phantom sounds on day 7 and underwent tinnitus spectrum characterization with the earplug still in place. The spectra showed that the phantom sounds were perceived predominantly as high-pitched, corresponding to the frequency range most affected by the earplug. In all cases, the auditory phantom disappeared when the earplug was removed, indicating a causal relation between auditory deprivation and phantom sounds. This relation matches the predictions of our computational model of tinnitus development, which proposes a possible mechanism by which a stabilization of neuronal activity through homeostatic plasticity in the central auditory system could lead to the development of a neuronal correlate of tinnitus when auditory nerve activity is reduced due to the earplug.

Computational models of neurophysiological correlates of tinnitus.

The understanding of tinnitus has progressed considerably in the past decade, but the details of the mechanisms that give rise to this phantom perception of sound without a corresponding acoustic stimulus have not yet been pinpointed. It is now clear that tinnitus is generated in the brain, not in the ear, and that it is correlated with pathologically altered spontaneous activity of neurons in the central auditory system. Both increased spontaneous firing rates and increased neuronal synchrony have been identified as putative neuronal correlates of phantom sounds in animal models, and both phenomena can be triggered by damage to the cochlea. Various mechanisms could underlie the generation of such aberrant activity. At the cellular level, decreased synaptic inhibition and increased neuronal excitability, which may be related to homeostatic plasticity, could lead to an over-amplification of natural spontaneous activity. At the network level, lateral inhibition could amplify differences in spontaneous activity, and structural changes such as reorganization of tonotopic maps could lead to self-sustained activity in recurrently connected neurons. However, it is difficult to disentangle the contributions of different mechanisms in experiments, especially since not all changes observed in animal models of tinnitus are necessarily related to tinnitus. Computational modeling presents an opportunity of evaluating these mechanisms and their relation to tinnitus. Here we review the computational models for the generation of neurophysiological correlates of tinnitus that have been proposed so far, and evaluate predictions and compare them to available data. We also assess the limits of their explanatory power, thus demonstrating where an understanding is still lacking and where further research may be needed. Identifying appropriate models is important for finding therapies, and we therefore, also summarize the implications of the models for approaches to treat tinnitus.

Development of hyperactivity after hearing loss in a computational model of the dorsal cochlear nucleus depends on neuron response type.

Cochlear damage can change the spontaneous firing rates of neurons in the dorsal cochlear nucleus (DCN). Increased spontaneous firing rates (hyperactivity) after acoustic trauma have been observed in the DCN of rodents such as hamsters, chinchillas and rats. This hyperactivity has been interpreted as a neural correlate of tinnitus. In cats, however, the spontaneous firing rates of DCN neurons were not significantly elevated after acoustic trauma. Species-specific spontaneous firing rates after cochlear damage might be attributable to differences in the response types of DCN neurons: In gerbils, type III response characteristics are predominant, whereas in cats type IV responses are more frequent. To address the question of how the development of hyperactivity after cochlear damage depends on the response type of DCN neurons, we use a computational model of the basic circuit of the DCN. By changing the strength of two types of inhibition, we can reproduce salient features of the responses of DCN neurons. Simulated cochlear damage, which decreases the activity of auditory nerve fibers, is assumed to activate homeostatic plasticity in projection neurons (PNs) of the DCN. We find that the resulting spontaneous firing rates depend on the response type of DCN PNs: PNs with type III and type IV-T response characteristics may become hyperactive, whereas type IV PNs do not develop increased spontaneous firing rates after acoustic trauma. This theoretical framework for the mechanisms and circumstances of the development of hyperactivity in central auditory neurons might also provide new insights into the development of tinnitus.

Tinnitus in men, mice (as well as other rodents), and machines.

The phantom auditory sensation of tinnitus is now studied in humans, animals, and computer models, and our understanding of how tinnitus is triggered and which neural mechanisms give rise to the phantom sensation in the brain has increased considerably. In most cases, tinnitus is associated with hearing loss, and even tinnitus patients with normal hearing thresholds might have cochlear damage that is not detected through conventional audiometry, as has been recently shown through auditory brainstem response measurements. Animals show behavioural signs of tinnitus after induction of hearing loss, indicating a causal relation. Moreover, surgical reduction of hearing loss in otosclerosis can reduce or even abolish tinnitus. However, hearing loss does not always lead to tinnitus. Psychophysical measurements have indicated that certain types of cochlear damage might be more closely linked to tinnitus than others. Recent animal studies have used behavioural testing to distinguish between animals with and without tinnitus after noise exposure. Comparisons between these groups of animals have helped identify neural correlates of tinnitus as well as factors that could represent a predisposition for tinnitus. Human neuroimaging studies have also begun to separate the neural signature of tinnitus from other consequences of hearing loss. The functional mechanisms that could underlie tinnitus development tinnitus have been analysed in computational modelling studies, which indicate that tinnitus could be a side-effect of the brains attempt to compensate for hearing loss. Even though causal treatments for tinnitus are currently not available, hearing aids can provide considerable benefit when used in conjunction with counselling, tinnitus retraining therapy or cognitive behavioural therapy. Finally, animal studies demonstrate that the development of chronic noise-induced tinnitus might be prevented through timely interventions after noise exposure. This article is part of a Special Issue entitled .

audiometric characteristics of hyperacusis patients

Hyperacusis is a frequent auditory disorder where sounds of normal volume are perceived as too loud or even painfully loud. There is a high degree of co-morbidity between hyperacusis and tinnitus, most hyperacusis patients also have tinnitus, but only about 30–40% of tinnitus patients also show symptoms of hyperacusis. In order to elucidate the mechanisms of hyperacusis, detailed measurements of loudness discomfort levels (LDLs) across the hearing range would be desirable. However, previous studies have only reported LDLs for a restricted frequency range, e.g., from 0.5 to 4 kHz or from 1 to 8 kHz. We have measured audiograms and LDLs in 381 patients with a primary complaint of hyperacusis for the full standard audiometric frequency range from 0.125 to 8 kHz. On average, patients had mild high-frequency hearing loss, but more than a third of the tested ears had normal hearing thresholds (HTs), i.e., ≤20 dB HL. LDLs were found to be significantly decreased compared to a normal-hearing reference group, with average values around 85 dB HL across the frequency range. However, receiver operating characteristic analysis showed that LDL measurements are neither sensitive nor specific enough to serve as a single test for hyperacusis. There was a moderate positive correlation between HTs and LDLs (r = 0.36), i.e., LDLs tended to be higher at frequencies where hearing loss was present, suggesting that hyperacusis is unlikely to be caused by HT increase, in contrast to tinnitus for which hearing loss is a main trigger. Moreover, our finding that LDLs are decreased across the full range of audiometric frequencies, regardless of the pattern or degree of hearing loss, indicates that hyperacusis might be due to a generalized increase in auditory gain. Tinnitus on the other hand is thought to be caused by neuroplastic changes in a restricted frequency range, suggesting that tinnitus and hyperacusis might not share a common mechanism.

Increased intensity discrimination thresholds in tinnitus subjects with a normal audiogram

Recent auditory brain stem response measurements in tinnitus subjects with normal audiograms indicate the presence of hidden hearing loss that manifests as reduced neural output from the cochlea at high sound intensities, and results from mice suggest a link to deafferentation of auditory nerve fibers. As deafferentation would lead to deficits in hearing performance, the present study investigates whether tinnitus patients with normal hearing thresholds show impairment in intensity discrimination compared to an audiometrically matched control group. Intensity discrimination thresholds were significantly increased in the tinnitus frequency range, consistent with the hypothesis that auditory nerve fiber deafferentation is associated with tinnitus.