A comparison between tinnitus and
A comparison between tinnitus and controls subjects showed increased activity in the left AUD and PHC for the gamma frequency band. The link between gamma band activity in the AUD and tinnitus has been identified using both EEG (van der Loo et al., 2009) and MEG (Weisz et al., 2005, 2007). This is supported by a positive correlation found in the present study between the tinnitus loudness and the activity in left AUD for the gamma frequency, confirming previous results (De Ridder et al., 2015; van der Loo et al., 2009). Further research showed however that the tinnitus percept might have a different generating mechanism depending on the amount of hearing loss (Vanneste et al., 2016). That is, the PHC, which is involved in auditory memory, becomes involved in tinnitus with more severe hearing loss (De Ridder et al., 2006, 2011; Engelien et al., 2000). This is in accordance with the recently proposed Bayesian model for tinnitus that describes a putative multiphase compensation mechanism linking auditory deafferentation to tinnitus (De Ridder et al., 2014a; Vanneste et al., 2016). Our data support this hypothesis in tinnitus patients with severe hearing loss by showing increased gamma activity in the PHC that correlates with tinnitus loudness (De Ridder et al., 2015). Previous studies on the effect of COMT polymorphism have suggested the importance of PFC dopamine to sensory gating. Recent research shows that healthy subjects who are Met carriers have poorer gating compared to the Val/Val E64 (Majic et al., 2011). The poorer gating in Met carriers corroborates our findings. Tinnitus patients perceive their tinnitus as louder, which might be related to a poorer pgACC-associated gating mechanism. Indeed, Met carriers exhibit increased activity in the pgACC for the theta frequency band, and the COMT polymorphism is known to be a crucial component for determining pgACC activity (Larisch et al., 1999). However, it is also possible that these changes in Met carriers are due increased hearing loss. Furthermore, both the AUD and PHC send and receive input to and from other cortical areas including the pgACC (Drabant et al., 2006). This is in line with our findings demonstrating increased input from both the AUD and PHC to the pgACC in tinnitus patients who are Met carriers. In addition, we find a strong association between activity in the AUD and PHC→pgACC with the level of tinnitus loudness. It has already been suggested that the pgACC in Met carriers should be able to process a high amount of input from sensory cortices (i.e. AUD and PHC) due to the increased dopaminergic neurotransmission (Majic et al., 2011). This could explain why we see increased activity in the pgACC for the theta frequency band and fits with the idea that the pgACC may open the sensory gate filter to utilize the high processing capacity for sensory input in cases of high PFC dopamine flux driven by COMT genetic variants (Majic et al., 2011). Another possible explanation could be that there is increased input of auditory information in the dACC and that tinnitus is the result of an imbalance between tinnitus-provoking activity in the dACC and tinnitus-suppressing activity in the pgACC, analogous to what has been described for pain in fibromyalgia (De Ridder et al., 2017). The rationale behind this idea is that the pgACC attempts to counterbalance the increased tinnitus-provoking input by increasing its suppression, but not enough to eliminate the imbalance. At the same time, we see decreased connectivity from the pgACC to both the AUD and PHC in Met-carrier tinnitus individuals, which would be in keeping with the second proposal, i.e. that the pgACC is deficient in its tinnitus-suppressive effect. This is further supported by the fact that Met carriers demonstrate a negative correlation between the putative inhibitory information going from the pgACC to both the left AUD and the left PHC, in other words, the weaker the connectivity from pgACC to the AUD and PHC, the louder patients perceive their tinnitus. Mechanistically, COMT has been shown to play an important role in top-down modulation targeting the AUD and PHC (Gallinat et al., 2002; Winterer et al., 2006). Met carriers have decreased coupling between the anterior pgACC and PHC in comparison to the Val/Val genotype (Meyer et al., 2016; Tian et al., 2013; Tunbridge et al., 2013), which fits with the fact that the medial PFC and PHC are the regions identified as having the largest effect of COMT as demonstrated by fMRI (Drabant et al., 2006) and are known to show the most abundant expressions of COMT (Chen et al., 2004; Masuda et al., 2003; Matsumoto et al., 2003). This fits with the ‘noise-cancellation system’ hypothesis (Rauschecker et al., 2010, 2015). Due to a deficiency in the pgACC, the thalamic reticular nucleus is hypothesized not to inhibit the highly selective and frequency-specific information transmission from the auditory thalamus to the AUD (Rauschecker et al., 2015; Yu et al., 2009).