Subjective tinnitus is defined as an auditory perception in the absence of any physically identifiable source for it. Almost everyone will experience some form of auditory phantom perceptions such as tinnitus at least once in their lifetime; in most of the cases this sensation vanishes within seconds or minutes. However, in 5 - 10% of the population in western societies the tinnitus persists for more than six months and usually remains chronic [1]. Those patients hear a constant ringing, buzzing or hissing in the ear and this perception is especially dominant when the patient is resting in a quiet environment. About 1 - 3% of the general population experience tinnitus as bothersome and complain that it affects their quality of life. Problems can include difficulties concentrating at work, a decrease in their social life, depression, insomnia or anxiety [2].

Tinnitus is typically associated with substantial damage to the hearing system such as a noise trauma or chronic noise exposure. This damage leads to plastic changes at various levels of the central auditory system and consequently enhanced neuronal synchrony and spontanous firing rate within the central auditory system. These changes have been well documented in animal and human studies and can be caused by different pathologies [3–7]. However, the mere hyperactivity of the central auditory system does not explain the diversity of tinnitus symptoms and the variability of the subjective tinnitus distress between patients. Thus, existing theories have stressed the importance of higher order association brain areas that could be involved in the processing of the tinnitus [4, 7, 8]. Cortical areas such as the frontal and the parietal lobe have been suggested to take part in a long-range neuronal network that is involved in the integration of sensory and emotional aspects of the tinnitus [4, 7, 8]. Furthermore it has been hypothesized that top-down mechanisms of this higher order network could modulate the activity of the auditory cortex [8]. This is in keeping with the model of the global neuronal workspace as suggested by Deheane and colleagues [9, 10]. This global neuronal workspace is distributed over distant areas of the cortex, mainly in the parietal lobe, the frontal, and the cingulate cortex. According to this framework, conscious perception requires neuronal activity of the sensory areas together with an entry into this workspace realized by long-range cortical coupling. Top-down influence from the global workspace on the sensory cortices amplifies the neuronal activity within the respective sensory area. Using magnetoencephalographic recordings in the resting state we aimed to explicitly test these assumptions: 1) Is there neuromagnetic evidence for alterations of long-range cortical networks in tinnitus during the resting state? What brain areas and frequency bands are involved in this network ? 2) Is there evidence for a top-down influence of this global network on the auditory cortex and does it relate to the subjective degree of tinnitus distress ?

Abnormal patterns of long-range cortical coupling have been found in other pathologies and significantly contributed to their understanding. For instance, Le van Quyen et al. [11] found for the pre-ictal phase in epilepsy a decrease of long-range synchrony with the epileptic focus and this isolation was accompanied by an increase of local synchrony within the epileptic focus. Uhlhaas and colleagues [12] investigated schizophrenic patients during a Gestalt perception task and discovered a reduction of beta-band phase synchrony that might be related to their impairment in grouping stimulus elements together to form a coherent percept. Silberstein et al. [13] reported an increase of cortico-cortical coupling in Parkinson's disease that correlated with the strength of Parkinsonism. Therapeutic interventions such as the application of L-dopa or electrical stimulation of the subthalamic nucleus resulted in a reduction of the cortico-cortical coupling and Parkinson symptoms.

Resting-state recordings, collected when the participant is instructed 'to do nothing', are characterized by widely distributed networks of coherent brain activations [14–17]. Disturbances of this default network have been detected in disorders such as Alzheimer's or Parkinson's disease [13, 18]. Since chronic tinnitus sufferers report an ongoing perception of the tinnitus sound that is most prominent when the environment is quiet, we expected to find abnormalities in the long-range couplings under resting conditions.

To investigate these abnormalities in magnetoencephalographic recordings we used a beamforming technique to reconstruct the brain activity in the source space and investigated the strength of coupling between them. Partial directed coherence (PDC) is a new approach to measure the effective coupling between multivariate time series. It is based on the concept of Granger causality and captures the direction of the information flow in the frequency domain [19, 20]. Several groups have applied this concept successfully to investigate directed coherence between cortical regions: Supp et al. reported differences in the directed information flow during an object recognition task of familiar and unfamiliar objects using Electroencephalography (EEG) [21]; Babiloni et al. investigated directed cortical coherence patterns during commercial spots and emotional spots [22], and Gross et al. also used source reconstruction combined with PDC to analyze directed interareal communication using Magnetoencephalography (MEG) [23]. In the present study we used PDC to analyze the directed coupling between all pairs of voxels in a frequency range from 2 to 100 Hz.

Networks in general are comprised by two elements: nodes (here: voxels) and the links (here: coherence) between them. The importance of a node within this network varies with the number of connections it entertains with other nodes: i.e. a node with a large number of links receives information from many other nodes and/or influences many other nodes. These core structures within a network are called hubs and can be operationalized simply by counting the number of links (this is called the degree of the hub/node). In directed networks, the information on the directionality of the information flow is retained. The inflow to a voxel indicates that the activity of this voxel is driven by another voxel. Accordingly, a hub with a strong outflow describes that this voxel influences the activity of many other voxels (Figure 1). With this information we can identify the hubs within the network that are characterized by a strong outflow and/or by a strong inflow.

In this study, we modeled the resting-state networks in tinnitus and controls by pinpointing the core structures of inflow and outflow. First, we compared the inflow and outflow between the tinnitus and the control group and found differences in the long-range cortical networks under rest. Second, we correlated the strength of the inflow and outflow with the subjective strength of the tinnitus distress. We found that the inflow in the left and the right temporal cortex correlated positively with tinnitus distress. We interpret this result as reflecting the top-down influence on the auditory cortex that modulates tinnitus distress.

In this study we found alterations in the functional coupling of long-range cortical networks between tinnitus and healthy control participants. Within this resting brain network we found regions with altered outflow and regions with altered inflow characteristics. A strong outflow in this context indicates that this brain area considerably influences the activity of other brain structures. In the tinnitus group two brain regions were identified with stronger outflow and one site with a weaker outflow. Stronger outflows were located in the prefrontal cortex and in the posterior part (parieto-occipital/occipital) of the brain. The weaker outflow was found in the orbitofrontal cortex. All of these changes in the outflow behavior were found for the gamma frequency band above 30 Hz. A strong inflow means that this brain area is strongly driven by other brain regions. With respect to the inflow characteristics we found two sites with significant group differences. The orbitofrontal cortex was receiving more inflow in the high frequency gamma range in the tinnitus group compared to the control group. Posterior parts of the cortex were receiving less inflow from other brain areas in a broad frequency range that included delta, theta, alpha, low beta and gamma frequencies. Furthermore, we found that the inflow to the temporal cortices correlates positively with the subjective ratings of the tinnitus distress. The more the activity in the temporal cortices was driven by other brain regions the stronger the subjective distress reported by the tinnitus subjects. Additionally, we also demonstrate that the inflow to the temporal cortex mainly originates from the prefrontal cortex and the posterior part of the brain; both are structures that we have characterized with a strong outflow within this network.

Thus we show significant alterations of the resting-state network in tinnitus. Although this was suggested earlier, empirical evidence was lacking to date. The prefrontal cortex, the orbitofrontal cortex, and the parieto-occipital region are important components within this network. The importance of the prefrontal cortex has previously been hypothesized by Jastreboff [4], who suggested that the prefrontal cortex integrates sensory and emotional aspects of tinnitus. In the present study we found that the prefrontal cortex in tinnitus strongly influences other brain regions of the network. In the 1960s it was shown that a disconnection of the prefrontal cortex results in a reduction of the annoyance of the tinnitus in most of the surviving patients [25]. Measuring the regional cerebral blood flow (rCBF) with Positron Emission Tomography (PET), Mirz and colleagues revealed a reduction of rCBF in the prefrontal cortex when the tinnitus was suppressed by lidocaine or masking [6]. Examining healthy volunteers, the same research group demonstrated that stimulation with an aversive sound leads to an increase in rCBF in the prefrontal cortex [26]. Kleinjung and colleagues [27] showed that tinnitus treatment with repetitive Transcranial Magnetic Stimulation (rTMS) applied on the temporal cortex can be enhanced by additionally stimulating the prefrontal cortex. Weisz et al. [7] reported that a reduction of alpha power and an enhancement of delta power in the prefrontal cortex correlates with tinnitus distress. The orbitofrontal cortex (OFC) in the tinnitus sample of the current study was characterized by enhanced influx from other regions and reduced output. The role of the orbitofrontal cortex in tinnitus has not been studied so far. Since other studies indicate that the OFC is part of the reward system [28–30], it is possible that it integrates the aversive information of the perceived tinnitus. This role of the OFC in this recording, however, remains speculative. The next cluster in this network was located in the posterior part of the brain including the occipital cortex, the parietal cortex, and the posterior cingulum. The outflow of this cluster was stronger in tinnitus subjects than in control participants. Another cluster approximately at the same position, but slightly more anterior was found to be significant for reduced inflow. Puzzling here is the outflow of the visual cortex. This might result from the coarse resolution with a voxel size of 2 cm that we used here. Since we used a standard-volume for all participants this adds imprecision to the mapping of the hubs. In a recently suggested model by Dehaene and colleagues, the parietal cortex and cingulate cortices have been associated with the global neuronal workspace and in the following we want to interpret the results in light of this framework.

This framework asserts the existence of workspace neurons that are distributed over the whole cortex, however, mainly in the parietal lobe, the frontal, the cingulate cortex and the sensory systems [9, 10]. In order to form a conscious percept of a stimulus, two conditions are required: First, neuronal activity of the sensory cortex of the respective modality, and. second, an entry into the global neuronal workspace and thus long-range coupling between the widely distributed workspace neurons. According to this model, coupling within this fronto-parietal-cingulate network is needed for conscious perception (i.e. awareness of the stimulus). Activity of the sensory areas without this coupling would remain unconscious. In the present study, participants in the tinnitus group all reported a continuous perception of the tinnitus tone while the healthy participants in the control group did not report such a perception. Hence we would expect to find significant group differences in the coupling strength between global workspace neurons. The framework of the global workspace does not make any predictions on the frequency bands involved in this long-range cortical network. With the present study we found the inflow/outflow effects mainly in the gamma frequency range. This is in line with many other studies finding inter-regional coupling in the gamma frequency range and demonstrating its functional importance in the integration of information from widely distributed brain regions: Miltner et al. [31] revealed enhanced gamma band coupling during associative learning; Melloni et al. [32] used different masks to manipulate whether a test stimuli was visible or invisible to the participants. They detected significant differences of gamma phase locking between the visible and the invisible condition. In another study Supp and colleagues [21] visually presented familiar and unfamiliar objects and found different patterns of gamma long-range coupling between the two conditions.

Another assumption of the global workspace hypothesis is that top-down influence from the global workspace to the respective sensory region amplifies the neuronal activity there [9, 10]. A top-down amplification of the neuronal activity in the auditory cortex in tinnitus has also been hypothesized earlier [8]. Indeed we found a significant correlation between the inflow to the temporal cortices and the subjective rating of the tinnitus distress: Tinnitus subjects with a stronger inflow to the temporal regions, report stronger distress. This explains why it has not been possible to reveal significant group differences between tinnitus and control participants regarding the temporal cortices. Since the degree of inflow to the temporal cortex of the tinnitus group was modulated by the tinnitus distress the variance in the tinnitus group was enhanced and the group difference did not reach significance. The outflow of the temporal cortices did not correlate with tinnitus distress. In a post-hoc analysis we were interested in the origin of this input to the temporal lobe, which we detected to stem largely from the prefrontal cortex, the parieto-occipital region, and regions adjacent to the left and right temporal cluster respectively. Thus, the top-down influence on the temporal cortex originates to a large extent from the prefrontal and the posterior clusters - clusters having been characterized before by an enhanced outflow in tinnitus. Because of methodological constraints with relatively large voxel sizes, a precise localization of the inflow cluster to specific anatomical structures within the temporal cortex is not possible. However, the localization of the maxima within the temporal clusters suggest that these clusters represents, at least partially, the auditory cortex. An involvement of other temporal structures (e.g. the hippocampus and parahippocampus) is also likely and cannot be excluded.

In summary, we have found alterations in the long-range functional network in tinnitus subjects under rest which we assert to be related to the conscious perception of the distressing tinnitus tone. This network exerts top-down influence on the auditory cortices. The strength of this influence is associated with the subjective strength of the tinnitus distress. Repetitive Transcranial Magnetic Stimulation (rTMS) aims to reduce the hyperactivity in the auditory cortex which leads to a reduction of tinnitus loudness [33–37], however a complete relief of tinnitus is rare. On the other hand, cognitive therapies are also able to reduce tinnitus symptoms partially [38, 39] and in light of the current study it can be argued that cognitive therapies alter the tinnitus-related global network and thus reduce the top-down influence of the global network on the temporal cortex. Overall we want to stress the importance of combining both branches of tinnitus therapy. Conceptually, a reduction of the hyperactivity in the auditory cortex cannot eliminate the tinnitus if the global network is still active and drives the tinnitus-related temporal activity. However, a reduction of the tinnitus-related global network activity cannot eliminate the tinnitus either if there is still an untreated abnormal pattern of spontaneous activity in the temporal cortex. It is hypothesized that sensory activity above a certain threshold can enter the global workspace in a bottom-up manner [9, 10]. Thus, tinnitus therapy needs to fight on two frontlines at the same time: Reducing the hyperactivity in the auditory cortex on the one hand (e.g. via rTMS or Neurofeedback) and changing the global network on the other hand (e.g. via Tinnitus Retraining or meditation techniques).