Aberrant Auditory Prediction Patterns Robustly Characterize Tinnitus

Reviewer #1 (Public Review):

This work presents a replicable difference in predictive processing between subjects with and without tinnitus. In two independent MEG studies and using a passive listening paradigm, the authors identify an enhanced prediction score in tinnitus subjects compared to control subjects. In the second study, individuals with and without tinnitus were carefully matched for hearing levels (next to age and sex), increasing the probability that the identified differences could truly be attributed to the presence of tinnitus. Results from the first study could successfully be replicated in the second, although the effect size was notably smaller.

Throughout the manuscript, the authors provide a thoughtful interpretation of their key findings and offer several interesting directions for future studies. Their conclusions are fully supported by their findings. Moreover, the authors are sufficiently aware of the inherent limitations of cross-sectional studies.

Strengths:

The robustness of the identified differences in prediction scores between individuals with and without tinnitus is remarkable, especially as successful replication studies are rare in the tinnitus field. Moreover, the authors provide several plausible explanations for the decline of the effect size observed in the second study.

The rigorous matching for hearing loss, in addition to age and sex, in the second study is an important strength. This ensures that the identified differences cannot be attributed to differences in hearing levels between the groups.

The used methodology is explained clearly and in detail, ensuring that the used paradigms may be employed by other researchers in future studies. Moreover, the registering of the data collection and analysis methods for Study 2 as a Registered Report should be commended, as the authors have clearly adhered to the methods as registered.

Weaknesses:

Although the authors have been careful to match their experimental groups for age, sex, and hearing loss, there are other factors that may confound the current results. For example, subjects with tinnitus might present with psychological comorbidities such as anxiety and depression. The authors' exclusion of distress as a candidate for explaining the found effects is based solely on an assessment of tinnitus-related distress, while it is currently not possible to exclude the effects of elevated anxiety or depression levels on the results. Additionally, as the authors address in the discussion, the presence of hyperacusis may also play a role in predictive processing in this population.

The authors write that sound intensity was individually determined by presenting a short audio sequence to the participants and adjusting the loudness according to an individual pleasant volume. Neural measurements made during listening paradigms might be influenced by sound intensity levels. The intensity levels chosen by the participants might therefore also have an effect on the outcomes. The authors currently do not provide information on the sound intensity levels in the experimental groups, making it impossible to assess whether sound intensity levels might have played a role.

Reviewer #2 (Public Review):

Summary:

This study aimed to test experimentally a theoretical framework that aims to explain the perception of tinnitus, i.e., the perception of a phantom sound in the absence of external stimuli, through differences in auditory predictive coding patterns. To this aim, the researchers compared the neural activity preceding and following the perception of a sound using MEG in two different studies. The sounds could be highly predictable or random, depending on the experimental condition. They revealed that individuals with tinnitus and controls had different anticipatory predictions. This finding is a major step in characterizing the top-down mechanisms underlying sound perception in individuals with tinnitus.

Strengths:

This article uses an elegant, well-constructed paradigm to assess the neural dynamics underlying auditory prediction. The findings presented in the first experiment were partially replicated in the second experiment, which included 80 participants. This large number of participants for an MEG study ensures very good statistical power and a strong level of evidence. The authors used advanced analysis techniques - Multivariate Pattern Analysis (MVPA) and classifier weights projection - to determine the neural patterns underlying the anticipation and perception of a sound for individuals with or without tinnitus. The authors evidenced different auditory prediction patterns associated with tinnitus. Overall, the conclusions of this paper are well supported, and the limitations of the study are clearly addressed and discussed.

Weaknesses:

Even though the authors took care of matching the participants in age and sex, the control could be more precise. Tinnitus is associated with various comorbidities, such as hearing loss, anxiety, depression, or sleep disorders. The authors assessed individuals' hearing thresholds with a pure tone audiogram, but they did not take into account the high frequencies (6 kHz to 16 kHz) in the patient/control matching. Moreover, other hearing dysfunctions, such as speech-in-noise deficits or hyperacusis, could have been taken into account to reinforce their claim that the observed predictive pattern was not linked to hearing deficits. Mental health and sleep disorders could also have been considered more precisely, as they were accounted for only indirectly with the score of the 10-item mini-TQ questionnaire evaluating tinnitus distress. Lastly, testing the links between the individuals' scores in auditory prediction and tinnitus characteristics, such as pitch, loudness, duration, and occurrence (how often it is perceived during the day), would have been highly informative.