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Mapping Cortical Hubs In Tinnitus Using Magnetoencephalography (MEG)

The current investigation utilized magnetoencephalography to map cortical hubs in tinnitus. Tinnitus is defined as an auditory perception in the absence of any physically identifiable source. 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].

Background (Continued)
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 spontaneous 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].

(click to enlarge) Illustration of a directed network and the hubs within this network. Left: The nodes are labeled with the hubdegree of the outflow (counting the arrow tails), Right: The nodes are labeled with the hubdegree of the inflow (counting the arrow heads).

All of these hypotheses stay within 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.

(click to enlarge) Group difference for the outflow. The strength of outflow describes how much the activity within the respective voxel drives the activity of other brain regions. Four clusters were found with a significant group difference between tinnitus and control participants. In the upper three clusters, the outflow was greater for the tinnitus group. In the lower cluster, the outflow of the tinnitus group was reduced. The location of the clusters are shown in the coronal, sagittal and horizontal view. The right column displays the significant frequency range of the clusters.

Using magnetoencephalographic recordings in the resting state the researchers 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?

(click to enlarge) Group difference for the inflow. The strength of inflow describes how much the activity within the respective voxel is driven by the activity of other brain regions. Three clusters were found with a significant group difference between tinnitus and control participants. In the upper cluster, the inflow was greater for the tinnitus group. In the lower two clusters, the inflow of the tinnitus group was reduced. The location of the clusters are shown in the coronal, sagittal and horizontal view. The right column displays the significant frequency range.

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]. 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.

(click to enlarge) Correlation of the strength of inflow with the subjective rating of the tinnitus distress. The inflow to voxels in the left and the right temporal cortex correlated positively with the subjective strength of the tinnitus distress. No significant correlations between the outflow and the distress were found.

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.

(click to enlarge) Location and frequency band of the inflow-clusters that correlated with the individual tinnitus distress. The stronger the inflow to the clusters, the stronger the subjective strength of tinnitus distress as assessed with a standard German Questionnaire. The location of the clusters are shown in the coronal, sagittal and horizontal view. The right column displays the significant frequency range of the clusters.

Summary
In this study, the researchers modeled the resting-state networks (the so called default network) in tinnitus and controls by pinpointing the core structures of inflow and outflow. They compared the inflow (figure 3) and outflow (figure 2) between the tinnitus and the control group and found differences in the long-range cortical networks under rest.

(click to enlarge) Regions with Top-Down Influence on the Temporal Clusters. The inflow to the clusters shown in figure 5 correlated with tinnitus distress. Here mapped the regions from where the top-down influence originated. Voxels with a low and putatively irrelevant influence on the clusters were masked.

The researchers further correlated the strength of the inflow and outflow with the subjective strength of the tinnitus distress (figure 4). They found three clusters of inflows that correlated positively with the subjective rating of the tinnitus distress. Stronger degrees of the inflows were associated with greater tinnitus distress. Cluster 1 was significant with P= 0.01 covering large parts of the left temporal cortex and also entering the frontal cortex to a small extent. The correlations were significant for the slow-wave frequencies, alpha, beta, and the lower gamma frequencies (2 – 46 Hz). Cluster 2 was located in the right temporal cortex and was significant with P= 0.05. In the frequency range of 14 – 42 Hz inflows correlated significantly with tinnitus distress. Cluster 3 was at the border of statistical significance (P= 0.07). This cluster was again located in the left temporal cortex and it covered the higher gamma frequencies from 80 – 98 Hz. See f Figure 5 for detailed imaging of locations and frequency bands.

The three clusters discussed above show meaningful correlations of the strength of inflow with the subjective rating of the tinnitus distress. Thus, activity within these clusters was driven by other regions of the brain. The final step of the analysis sought to determine the origin of the inflow. First, it was determined that these regions all received input from a large area in the frontal cortex, but with no influence from the right orbitofrontal cortex (Cluster 4 of the outflow; see Figure 2). Secondly, they all received influence from posterior voxels, approximately at the location of the outgoing clusters 1 and 3. Thirdly, they all received input from their directed neighborhood: The left temporal clusters (Cluster 1 and 3) received input from the adjacent left fronto-temporal region. Respectively, the right temporal clusters were influenced by the neighboring right fronto-temporal region.  In short, these findings were interpreted to reflect a top-down influence on the auditory cortex that modulates tinnitus distress (Figure 6).

Conclusion
In summary, alterations in the long-range functional network in tinnitus subjects under rest were found, which were asserted 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, the importance of combining both branches of tinnitus therapy needs to be highly stressed. 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).

Citation
Material adapted by CFisher from:
Winfried Schlee, Nadia Mueller, Thomas Hartmann, Julian Keil, Isabel Lorenz, & Nathan Weisz (2009). Mapping cortical hubs in tinnitus. BMC Biology, 7:80.

Reference
Please see the freely available original article for the extensive reference list. Numbered references in this current article match the references in the original article.

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