The mechanisms of tinnitus: perspectives from human functional neuroimaging

In this review, we highlight the contribution of advances in human neuroimaging to the current understanding of central mechanisms underpinning tinnitus and explain how interpretations of neuroimaging data have been guided by animal models. The primary motivation for studying the neural substrates of tinnitus in humans has been to demonstrate objectively its representation in the central auditory system and to develop a better understanding of its diverse pathophysiology and of the functional interplay between sensory, cognitive and affective systems. The ultimate goal of neuroimaging is to identify subtypes of tinnitus in order to better inform treatment strategies. The three neural mechanisms considered in this review may provide a basis for TI classification. While human neuroimaging evidence strongly implicates the central auditory system and emotional centres in TI, evidence for the precise contribution from the three mechanisms is unclear because the data are somewhat inconsistent. We consider a number of methodological issues limiting the field of human neuroimaging and recommend approaches to overcome potential inconsistency in results arising from poorly matched participants, lack of appropriate controls and low statistical power

Determination and evaluation of clinically efficient stopping criteria for the multiple auditory steady-state response technique

Background: Although the auditory steady-state response (ASSR) technique utilizes objective statistical detection algorithms to estimate behavioural hearing thresholds, the audiologist still has to decide when to terminate ASSR recordings introducing once more a certain degree of subjectivity. Aims: The present study aimed at establishing clinically efficient stopping criteria for a multiple 80-Hz ASSR system. Methods: In Experiment 1, data of 31 normal hearing subjects were analyzed off-line to propose stopping rules. Consequently, ASSR recordings will be stopped when (1) all 8 responses reach significance and significance can be maintained for 8 consecutive sweeps; (2) the mean noise levels were ≤ 4 nV (if at this “≤ 4-nV” criterion, p-values were between 0.05 and 0.1, measurements were extended only once by 8 sweeps); and (3) a maximum amount of 48 sweeps was attained. In Experiment 2, these stopping criteria were applied on 10 normal hearing and 10 hearing-impaired adults to asses the efficiency. Results: The application of these stopping rules resulted in ASSR threshold values that were comparable to other multiple-ASSR research with normal hearing and hearing-impaired adults. Furthermore, in 80% of the cases, ASSR thresholds could be obtained within a time-frame of 1 hour. Investigating the significant response-amplitudes of the hearing-impaired adults through cumulative curves indicated that probably a higher noise-stop criterion than “≤ 4 nV” can be used. Conclusions: The proposed stopping rules can be used in adults to determine accurate ASSR thresholds within an acceptable time-frame of about 1 hour. However, additional research with infants and adults with varying degrees and configurations of hearing loss is needed to optimize these criteria

Using Auditory Steady State Responses to Outline the Functional Connectivity in the Tinnitus Brain

BACKGROUND: Tinnitus is an auditory phantom perception that is most likely generated in the central nervous system. Most of the tinnitus research has concentrated on the auditory system. However, it was suggested recently that also non-auditory structures are involved in a global network that encodes subjective tinnitus. We tested this assumption using auditory steady state responses to entrain the tinnitus network and investigated long-range functional connectivity across various non-auditory brain regions. METHODS AND FINDINGS: Using whole-head magnetoencephalography we investigated cortical connectivity by means of phase synchronization in tinnitus subjects and healthy controls. We found evidence for a deviating pattern of long-range functional connectivity in tinnitus that was strongly correlated with individual ratings of the tinnitus percept. Phase couplings between the anterior cingulum and the right frontal lobe and phase couplings between the anterior cingulum and the right parietal lobe showed significant condition x group interactions and were correlated with the individual tinnitus distress ratings only in the tinnitus condition and not in the control conditions. CONCLUSIONS: To the best of our knowledge this is the first study that demonstrates existence of a global tinnitus network of long-range cortical connections outside the central auditory system. This result extends the current knowledge of how tinnitus is generated in the brain. We propose that this global extend of the tinnitus network is crucial for the continuos perception of the tinnitus tone and a therapeutical intervention that is able to change this network should result in relief of tinnitus

Neural plasticity expressed in central auditory structures with and without tinnitus

Sensory training therapies for tinnitus are based on the assumption that, notwithstanding neural changes related to tinnitus, auditory training can alter the response properties of neurons in auditory pathways. To assess this assumption, we investigated whether brain changes induced by sensory training in tinnitus sufferers and measured by electroencephalography (EEG) are similar to those induced in age and hearing loss matched individuals without tinnitus trained on the same auditory task. Auditory training was given using a 5 kHz 40-Hz amplitude-modulated (AM) sound that was in the tinnitus frequency region of the tinnitus subjects and enabled extraction of the 40-Hz auditory steady-state response (ASSR) and P2 transient response known to localize to primary and non-primary auditory cortex, respectively. P2 amplitude increased over training sessions equally in participants with tinnitus and in control subjects, suggesting normal remodeling of non-primary auditory regions in tinnitus. However, training-induced changes in the ASSR differed between the tinnitus and control groups. In controls the phase delay between the 40-Hz response and stimulus waveforms reduced by about 10° over training, in agreement with previous results obtained in young normal hearing individuals. However, ASSR phase did not change significantly with training in the tinnitus group, although some participants showed phase shifts resembling controls. On the other hand, ASSR amplitude increased with training in the tinnitus group, whereas in controls this response (which is difficult to remodel in young normal hearing subjects) did not change with training. These results suggest that neural changes related to tinnitus altered how neural plasticity was expressed in the region of primary but not non-primary auditory cortex. Auditory training did not reduce tinnitus loudness although a small effect on the tinnitus spectrum was detected

Altered Cortical Oscillations: Investigations into a Putative Neural Correlate of Tinnitus

Abnormal cortical oscillations have been implicated in tinnitus generation. To gain further insight into this relationship, we performed two Experimental Series, both employing behavioural, pharmacological, and in vivo electrophysiological techniques in an animal model. To that end, we revealed three novel findings: (1) While exposure to 250 mg/kg sodium salicylate or transient loud noise induced behavioural evidence of tinnitus, these insults caused dissimilar effects on spontaneous cortical oscillations; (2) Despite these dissimilar effects, sodium salicylate and loud noise exposure caused similar deficits in the evoked oscillatory activity elicited by the auditory steady state response; and (3) Manipulation of medial geniculate body GABAergic inhibition is sufficient to alter spontaneous cortical oscillations, but does not induce tinnitus-like behaviour. Collectively, these findings suggest that there is no clear link between altered cortical oscillations and tinnitus, and the 40 Hz ASSR might be a useful tool for assessing the presence of tinnitus in animals

Illusory Percepts from Auditory Adaptation

Phenomena resembling tinnitus and Zwicker phantom tone are seen to result from an auditory gain adaptation mechanism that attempts to make full use of a fixed-capacity channel. In the case of tinnitus, the gain adaptation enhances internal noise of a frequency band otherwise silent due to damage. This generates a percept of a phantom sound as a consequence of hearing loss. In the case of Zwicker tone, a frequency band is temporarily silent during the presentation of a notched broad-band sound, resulting in a percept of a tone at the notched frequency. The model suggests a link between tinnitus and the Zwicker tone percept, in that it predicts different results for normal and tinnitus subjects due to a loss of instantaneous nonlinear compression. Listening experiments on 44 subjects show that tinnitus subjects (11 of 44) are significantly more likely to hear the Zwicker tone. This psychoacoustic experiment establishes the first empirical link between the Zwicker tone percept and tinnitus. Together with the modeling results, this supports the hypothesis that the phantom percept is a consequence of a central adaptation mechanism confronted with a degraded sensory apparatus

Illusory Percepts from Auditory Adaptation

Phenomena resembling tinnitus and Zwicker phantom tone are seen to result from an auditory gain adaptation mechanism that attempts to make full use of a fixed-capacity channel. In the case of tinnitus, the gain adaptation enhances internal noise of a frequency band otherwise silent due to damage. This generates a percept of a phantom sound as a consequence of hearing loss. In the case of Zwicker tone, a frequency band is temporarily silent during the presentation of a notched broad-band sound, resulting in a percept of a tone at the notched frequency. The model suggests a link between tinnitus and the Zwicker tone percept, in that it predicts different results for normal and tinnitus subjects due to a loss of instantaneous nonlinear compression. Listening experiments on 44 subjects show that tinnitus subjects (11 of 44) are significantly more likely to hear the Zwicker tone. This psychoacoustic experiment establishes the first empirical link between the Zwicker tone percept and tinnitus. Together with the modeling results, this supports the hypothesis that the phantom percept is a consequence of a central adaptation mechanism confronted with a degraded sensory apparatus

Applicability of subcortical EEG metrics of synaptopathy to older listeners with impaired audiograms

Emerging evidence suggests that cochlear synaptopathy is a common feature of sensorineural hearing loss, but it is not known to what extent electrophysiological metrics targeting synaptopathy in animals can be applied to people, such as those with impaired audiograms. This study investigates the applicability of subcortical electrophysiological measures associated with synaptopathy, i.e., auditory brainstem responses (ABRs) and envelope following responses (EFRs), to older participants with high-frequency sloping audiograms. The outcomes of this study are important for the development of reliable and sensitive synaptopathy diagnostics in people with normal or impaired outer-hair-cell function. Click-ABRs at different sound pressure levels and EFRs to amplitude-modulated stimuli were recorded, as well as relative EFR and ABR metrics which reduce the influence of individual factors such as head size and noise floor level on the measures. Most tested metrics showed significant differences between the groups and did not always follow the trends expected from synaptopathy. Age was not a reliable predictor for the electrophysiological metrics in the older hearing-impaired group or young normal-hearing control group. This study contributes to a better understanding of how electrophysiological synaptopathy metrics differ in ears with healthy and impaired audiograms, which is an important first step towards unravelling the perceptual consequences of synaptopathy.(C) 2019 Elsevier B.V. All rights reserved

Cortical mechanisms for tinnitus in humans /

PhD ThesisThis work sought to characterise neurochemical and neurophysiological processes underlying tinnitus in humans. The first study involved invasive brain recordings from a neurosurgical patient, along with experimental manipulation of his tinnitus, to map the cortical system underlying his tinnitus. Widespread tinnitus-linked changes in low- and high-frequency oscillations were observed, along with inter-regional and cross-frequency patterns of communication. The second and third studies compared tinnitus patients to controls matched for age, sex and hearing loss, measuring auditory cortex spontaneous oscillations (with magnetoencephalography) and neurochemical concentrations (with magnetic resonance spectroscopy) respectively. Unlike in previous studies not controlled for hearing loss, there were no group differences in oscillatory activity attributable to tinnitus. However, there was a significant correlation between gamma oscillations (>30Hz) and hearing loss in the tinnitus group, and between delta oscillations (1-4Hz) and perceived tinnitus loudness. In the neurochemical study, tinnitus patients had significantly reduced GABA concentrations compared to matched controls, and within this group there was a positive correlation between choline concentration (potentially linked to acetylcholine and/or neuronal plasticity) and both hearing loss, and subjective tinnitus intensity and distress. In light of present and previous findings, tinnitus may be best explained by a predictive coding model of perception, which was tested in the final experiment. This directly controlled the three main quantities comprising predictive coding models, and found that delta/theta/alpha oscillations (1-12Hz) encoded the precision of predictions, beta oscillations (12-30Hz) encoded changes to predictions, and gamma oscillations represented surprise (unexpectedness of stimuli based on predictions). The work concludes with a predictive coding model of tinnitus that builds upon the present findings and settles unresolved paradoxes in the literature. In this, precursor processes (in varying combinations) synergise to increase the precision associated with spontaneous activity in the auditory pathway to the point where it overrides higher predictions of ‘silence’.Medical Research Council Wellcome Trust and the National Institutes of Healt