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  • Tinnitus Met carriers with severe hearing loss perceive thei


    Tinnitus Met carriers with severe hearing loss perceive their tinnitus as being louder, which is associated with increased activity in the PHC, increased PHC→pgACC connectivity, as well as decreased pgACC→PHC connectivity. This indicates that Met carriers with severe hearing loss have increased tinnitus input as well as decreased tinnitus inhibition, as mentioned before. Previous studies have reported pgACC-mediated inhibition deficiencies in aggression (Buckholtz et al., 2008a), proneness to vertigo (Alsalman et al., 2016), and fibromyalgia (Jensen et al., 2013). That is, the pgACC sends an inhibitory projection to several other areas including the amygdala and PHC and thus might have a general stimulus-inhibition function (Buckholtz et al., 2008b; Vogt et al., 2001). This has been linked to negative feedback function in a Bayesian framework (De Ridder et al., 2016). In tinnitus with severe hearing loss, we see the imbalance explained by the connection with the PHC rather with the AUD. Notably, several studies report an effect of COMT Val158Met on the PHC as well as its connectivity to other Copanlisib areas (Bertolino et al., 2006; Meyer et al., 2016; Zhang et al., 2015). This further fits with the central concept of the Bayesian brain model for tinnitus that predicts that patients with severe hearing loss increasingly recruit auditory memory-related areas to fill in the missing information when local auditory cortical map plasticity cannot recruit it from the local Copanlisib cortical neighborhood (De Ridder et al., 2014a; Vanneste et al., 2016). This fits with the finding that in tinnitus with more severe hearing loss, the PHC becomes more involved as a tinnitus-generating mechanism, whereas in tinnitus without audiometric hearing loss the AUD should be more involved (Vanneste et al., 2016). The present study adds to this mechanistic explanation by identifying that severe hearing loss in combination with being a Met carrier makes the tinnitus percept louder due to a deficit in the pgACC-driven cancelation mechanism. It is important to acknowledge a second COMT (COMT2), which is related to COMT1 that regulates dopamine levels in the brain, is widely expressed in inner and outer hair cells of the cochlea. A mutation to a COMT2 shows defects in cochlear function in both mice and humans that are related to hearing loss or deafness phenotype (Du et al., 2008). Hence, it is possible that COMT can also be attributed to a peripheral component that affects hearing and tinnitus. Due to this association, it is possible that COMT could have an impact on tinnitus due to a hearing impairment that is not measurable with a pure tone audiogram (i.e. “hidden hearing loss”) but that might contribute to our findings. Furthermore, research suggests that the COMT Val158Met polymorphism influences the human experience of pain and may underlie interindividual differences in the adaptation and responses to pain and other stressful stimuli (Zubieta et al., 2003). Previous research also revealed the existence of an alternative neuronal pathway from the cochlea to the brainstem that is activated by tissue-damaging noise, possibly by type-II cochlear afferents, representing auditory nociception (Flores et al., 2015). As Met carriers are more sensitive to pain, it might be that these subjects respond in a different way to noise induced tinnitus in comparison to Val/Val homozygotes. Progress in finding a treatment for tinnitus has been hampered by the fact that tinnitus represents a highly heterogeneous condition (Schecklmann et al., 2012, 2013). Hence, it was suggested that there might be different subtypes of tinnitus. Our research fits with this idea, showing that there might be different subtypes of tinnitus depending on, for example, the underlying COMT genotype. Further studies should be performed evaluating these results with other functional imaging techniques as well as neuromodulation techniques to confirm this idea of subtyping. It has already been shown, for example, that the effect of tDCS on auditory hallucinations—which can be considered a complex form of tinnitus, analogous to hallucinosis (Vanneste et al., 2013)—depends on the COMT polymorphism (Wiegand et al., 2016).