Tinnitus is an acoustic phantom perception, defined as the subjective perception of a sound without a physical sound source. With a prevalence of up to 21% of the adult population (Fuller et al., 2020), it is a common phenomenon, which is associated with severe distress including psychiatric problems, sleep disturbances, concentration, and work impairment in 1%–3% of the population (Eggermont and Roberts, 2004; Cima et al., 2019). Clinical evidence suggests that in most cases tinnitus becomes chronic about 4 weeks after its first appearance (Wallhäusser-Franke et al., 2017). To date, no effective treatment exists mainly because processes generating and maintaining tinnitus are insufficiently understood (Langguth et al., 2019). It is widely accepted that tinnitus is initially elicited by damage of hair cells in the inner ear. Since the review by Baguley (2002) outlining that tinnitus persists after transection of the auditory nerve, it is accepted that tinnitus is generated within the central nervous system. Most research suggests that initial hearing loss triggers neuronal changes along the ascending auditory pathway leading to tinnitus. Tinnitus is associated with an increase in spontaneous activity, elevated bursting activity, reorganization of the cortical map, and an increase in neuronal synchrony (Shore et al., 2016). The role of neural synchrony is strongly supported by studies investigating abnormalities in oscillatory brain activity associated with tinnitus. At a cortical level it has been shown that oscillatory alpha activity is reduced in the auditory cortex of tinnitus patients (Weisz et al., 2005), while delta, theta, and gamma activity is increased in auditory cortical and subcortical areas (Llinas et al., 1999; Weisz et al., 2007). Counteracting pathological synchrony in the auditory system can indeed reduce tinnitus perception [e.g., increase of auditory alpha activity by neurofeedback or repetitive Transcranial Magnetic Stimulation (rTMS): Dohrmann et al., 2007; Müller et al., 2013; desynchronization of pathological brain activity and acoustic coordinated reset training: Tass et al., 2012; other TMS approaches: overview in Langguth et al., 2013]. However, results show great interindividual variability and rather small effect sizes. Furthermore, most studies did not control for hearing loss, so that it is still unclear whether changes in neuronal synchrony, especially in the high-frequency range, relate to the tinnitus percept itself or to hearing loss associated with tinnitus (Adjamian et al., 2012; Demopoulos et al., 2020).

Whether these neurophysiological alterations along the auditory pathway lead to chronic tinnitus perception, how loud or aversive tinnitus is experienced and if high psychological distress accompanies tinnitus perception depends on the co-activation of non-auditory brain networks involved in cognitive and emotional processes associated with tinnitus (de Ridder et al., 2014; Shore et al., 2016; Kleinjung and Langguth, 2020). In line with that, a multitude of studies found abnormalities in the activation of non-auditory brain regions, such as the anterior cingulate cortex (ACC), the amygdala, the insula, the (para)hippocampus and the parietal as well as the (orbitofrontal and dorsolateral) prefrontal cortex (Leaver et al., 2011; Maudoux et al., 2012; Roberts et al., 2013; McEwen et al., 2015; Rauschecker et al., 2015; Sedley et al., 2015; Minguillon et al., 2016; Mohsen et al., 2019) in tinnitus patients compared to normal-hearing controls. Accordingly, tinnitus perception and distress have been associated with aberrant oscillatory activity in low and high frequency bands in non-auditory, mainly frontal and limbic areas (Vanneste and de Ridder, 2012; Meyer et al., 2014; Lee et al., 2020).

Supporting the relevance of non-auditory influence on tinnitus, Lehner et al. (2013) revealed that multisite rTMS (prefrontal stimulation in addition to auditory stimulation) reduces tinnitus severity significantly longer (up to 3 months) compared to mere auditory stimulation.

Behavioral research emphasizes the association between perceived stress and tinnitus. During or after a period of high stress the probability to develop tinnitus increases significantly (Kleinjung and Langguth, 2020). Most interestingly, the correlation between tinnitus incidence and stress is as high as between tinnitus incidence and noise exposure (Baigi et al., 2011). Furthermore, chronic tinnitus deteriorates during exposure to stress (Langguth et al., 2007; Probst et al., 2016; Pupić-Bakrač and Pupić-Bakrač, 2020; Elarbed et al., 2021). Reducing stress through CBT, Progressive Muscle Relaxation, or Yoga can lead to reduced tinnitus severity and subjectively reported psychological distress (Weber et al., 2002; Hesser et al., 2012; Köksoy et al., 2018). Supporting the role of stress in tinnitus further, it should be emphasized that the above highlighted non-auditory regions associated with tinnitus overlap broadly with the stress network found in patients suffering from pain, functional somatic syndromes, and Posttraumatic Stress Disorder (PTSD). Such a stress network could maintain and reinforce undesired perception in tinnitus (de Ridder et al., 2011; Mohsen et al., 2019), similarly to processes observed in PTSD (Fagelson, 2007). The tied relationship between the depicted regions and stress exposure is further supported by recent studies that investigated structural neuronal changes associated with massive stress exposure. Wu et al. (2021) revealed a negative relation between the levels of perceived stress and gray matter volume of the orbitofrontal cortex, the insula and the amygdala in healthy adults indicating a detrimental effect of stress on neuronal structures.

Another line of rather recent research highlights the association between the immune system and chronic tinnitus. Tinnitus has been associated with an increased susceptibility to different physical comorbidities. A recent study by Basso et al. (2021), for instance, showed that patients with bothersome tinnitus suffer more frequently from physical comorbidities, such as cardiovascular disease, chronic shoulder pain, thyroid, or Ménière’s disease compared to non-bothersome tinnitus. A recent meta-analysis by Almufarrij and Munro (2021) states that 14.8 percent of Covid-19 patients report an onset or aggravation of tinnitus associated with their affection. The authors highlight beyond other possible causes the immune system as a potential mediator of the effect and state that, e.g., excessive production of proinflammatory cytokines may affect the audio-vestibular system (Degen et al., 2020). This is in line with evidence provided by Haider et al. (2020), who showed that the anti-inflammatory cytokine Interleukin-10 (IL-10) is significantly altered in patients suffering from chronic tinnitus compared to normal-hearing controls. Beyond, Wang et al. (2019) showed that tinnitus can be prevented by repressing the production of TNF-α (a cytokine engaged in most inflammation processes) in the auditory cortex of mice by medication. Peculiarities with regard to the immune system in tinnitus patients have also been reported in relation to stress (Mazurek et al., 2019). For example, Szczepek et al. (2014) found a positive correlation between TNF-α, perceived tinnitus loudness and stress. In line with that, Weber et al. (2002) showed that stress levels, tinnitus severity, and TNF-α levels reduced after relaxation training in tinnitus patients. These findings might be evidence for a link between inflammation processes triggered by the immune system and the above-described non-auditory, often stress-related, aspects of tinnitus.

A further immune system marker, which is related with chronic stress (Johnson and Zatorre, 2006; Juster et al., 2010) and is, therefore, highly relevant for studying the associations between chronic stress and inflammation in tinnitus, is C-reactive protein (CRP). CRP is an acute phase protein, which is synthesized in the liver. It is produced rapidly in response to inflammation, tissue damage, or vaccination and plays a key role in the innate immune system (Peisajovich et al., 2008; Perez, 2019). CRP levels are increased in patients with several diseases such as cancer, HIV, or cardiovascular diseases and elevated CRP levels are related with higher mortality (Li et al., 2017). Furthermore, there is first evidence that CRP levels are increased in chronic tinnitus (Kang et al., 2021).

Overall, it is well-known that chronic tinnitus is associated with stress and altered brain functioning. Furthermore, there is first evidence that the immune system is also altered in chronic tinnitus. Elevated immune system markers (e.g., pro-inflammatory cytokines such as IL-6 or acute phase proteins such as CRP), which are also associated with chronic stress. However, the link between brain activity and the immune system has not been investigated in chronic tinnitus so far. The aim of our study was, therefore, to investigate the association between brain activity in chronic tinnitus and the immune system (more precisely, the acute phase protein CRP).

The aim of our study was to investigate the association between resting state MEG brain activity and CRP levels in chronic tinnitus. We found a significant negative correlation between high gamma and CRP levels in the BA11 lateral cluster for the tinnitus group. This indicates that low orbitofrontal high gamma power was associated with high CRP. No significant clusters were found for other frequency bands (i.e., delta, theta, alpha, beta, and low gamma).

The decrease of high gamma power in the orbitofrontal cortex when CRP is high can be interpreted as a deactivation of the orbitofrontal cortex associated with high CRP levels. This interpretation is supported by studies showing that the level of high gamma power correlates positively with the BOLD response (Logothetis et al., 2001) and is closely related to the activation of neuronal populations in the orbitofrontal cortex (Rich and Wallis, 2017).

The orbitofrontal cortex is involved in higher order cognitive functions such as sensory inhibition (Ben Shalom and Bonneh, 2019), top-down attentional control (Kam et al., 2021), and emotional regulation (Rolls, 2017). In line with that, orbitofrontal dysfunction has been associated with problems in emotion regulation or impulsive control (fear processing: Hsieh and Chang, 2020; PTSD: Franz et al., 2020; depression: Davidson et al., 2002; methamphetamine dependence: Paulus et al., 2002; Attention-Deficit-Hyperactivity Disorder: Toplak et al., 2005). Moreover, a deactivation of the prefrontal cortex has been related to reduced positive affect (Kringelbach, 2005) and an increase in pain perception (Moont et al., 2011). A deactivation of the orbitofrontal cortex in tinnitus is, therefore, very likely to reflect top-down processes maintaining tinnitus through disinhibition of auditory perception (Ben Shalom and Bonneh, 2019), attentional processes (Kam et al., 2021), or emotional reinforcement (Rolls, 2017). Most interestingly, the orbitofrontal cortex is part of the tinnitus distress network (de Ridder et al., 2011; Elgoyhen et al., 2015; Leaver et al., 2016). Further support for the relationship between a dysfunction of the orbitofrontal cortex and tinnitus comes from voxel-based morphometry, e.g., Mühlau et al. (2006) who showed that the orbitofrontal gray-matter volume is reduced in patients suffering from chronic tinnitus compared to healthy controls. In line with that, Müller et al. (2013) found that the decrease of orbitofrontal gamma power is associated with an increase in tinnitus loudness. We hypothesize that the orbitofrontal cortex could be a major hub in transferring inflammation processes to the tinnitus network and thereby stimulate central neuronal processes that maintain tinnitus. This notion is supported by a study showing that taking Naltrexone, which reduces CRP levels and acts on μ-opioid receptors in the orbitofrontal cortex (amongst other regions) led to a significant reduction of tinnitus distress (Vanneste et al., 2013).

Interestingly, perceived stress was significantly higher in the tinnitus group compared to the control group and an association between CRP and PSS score was only found in the tinnitus group (as well as in the pooled sample). This could mean that, in tinnitus patients, chronic stress triggers inflammatory processes maintaining tinnitus in the central nervous system. Such a mechanism could explain how the above-described tight association between tinnitus and stress is operating in the brain and must be part of future research.

However, due to our cross-sectional design, the direction of the association (i.e., causation) between CRP levels and orbitofrontal gamma power remains unclear. Both directions are conceivable, i.e., inflammation could either cause or exacerbate the tinnitus symptoms, or intrusive tinnitus could raise CRP levels. For instance, hypofunction of the orbitofrontal cortex could disinhibit the tinnitus symptoms, leading to greater distress, which might impact upon stress and sleep, and thereby increasing inflammation. Moreover, a bi-directional or recursive relationship would also be possible. Nevertheless, our study highlights the importance of considering immune-brain communication in tinnitus research.

Our study is subject to some further limitations, of which the most important one is that we did not record MEG data from the control group. However, the significant differences in CRP levels and PSS scores between both groups which were both related with gamma power suggest that the pattern will be different for the controls. This must be investigated in future studies. Moreover, we would like to mention here that, due to the explorative nature of our study, we decided to use rigid statistics capable of testing predominantly large effects across the whole brain. This could have kept us blind for smaller effects in other brain regions or frequency bands. A more fine-grained examination of effects in other frequency bands, brain areas or communication patterns should be addressed in future studies.

Our study provides a number of starting points for future research. The first important next step is replicating our findings within a controlled design. Because our control group was not matched with regards to hearing loss, this should also be addressed in future studies. Moreover, the underlying mechanisms as well as the direction of the association between inflammation and gamma power in the orbitofrontal cortex and the association with stress (including psychological distress as well as physiological stress) must be investigated by means of longitudinal studies.

Despite the still open questions regarding directionality, our findings have important implications for the treatment of tinnitus because they suggest that inflammation-reducing treatments might be suitable. One possibility would be physical activity interventions, which have been shown to be well-suited for reducing CRP levels (Kaltenegger et al., 2021). In general, physical activity has been shown to be suitable for reducing distress, improve mental well-being, and change re-activity of biological stress systems (e.g., Fox, 1999; Huang et al., 2013; Becker et al., 2021b). A potential alternative would be drug treatments which reduce CRP levels, but very few drugs can reduce CRP without treating the underlying pathology (Pepys and Hirschfield, 2003). Overall, there is currently no gold standard for the treatment of chronic tinnitus and not every treatment can reduce the symptoms in every tinnitus patient. One reason for this is that the underlying pathology has not yet been fully understood in any case (Langguth et al., 2019). Our results, which emphasize the role of inflammation, make an important contribution in this direction and it should be investigated in future research whether the suggested inflammation-reducing treatments are indeed also suitable to decrease the tinnitus symptoms.

Our findings indicate that people with chronic tinnitus have higher CRP levels than healthy controls, which makes them particularly vulnerable. Moreover, our study highlights the role of the orbitofrontal cortex in chronic tinnitus and the importance of considering immune-brain communication in tinnitus research. Most importantly, our study emphasizes the potential of considering inflammation as part of the treatment of chronic tinnitus.

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Ethics Committee of the Friedrich-Alexander University of Erlangen. The patients/participants provided their written informed consent to participate in this study.

LB, NR, and NM-V contributed to conception and design of the study. AK collected the data. LB and NM-V analyzed the data and wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.