Unilateral tinnitus: changes in connectivity and response lateralization measured with FMRI

Abstract

Tinnitus is a percept of sound that is not related to an acoustic source outside the body. For many forms of tinnitus, mechanisms in the central nervous system are believed to play a role in the pathology. In this work we specifically assessed possible neural correlates of unilateral tinnitus. Functional magnetic resonance imaging (fMRI) was used to investigate differences in sound-evoked neural activity between controls, subjects with left-sided tinnitus, and subjects with right-sided tinnitus. We assessed connectivity patterns between auditory nuclei and the lateralization of the sound-evoked responses. Interestingly, these response characteristics did not relate to the laterality of tinnitus. The lateralization for left- or right ear stimuli, as expressed in a lateralization index, was considerably smaller in subjects with tinnitus compared to that in controls, reaching significance in the right primary auditory cortex (PAC) and the right inferior colliculus (IC). Reduced functional connectivity between the brainstem and the cortex was observed in subjects with tinnitus. These differences are consistent with two existing models that relate tinnitus to i) changes in the corticothalamic feedback loops or ii) reduced inhibitory effectiveness between the limbic system and the thalamus. The vermis of the cerebellum also responded to monaural sound in subjects with unilateral tinnitus. In contrast, no cerebellar response was observed in control subjects. This suggests the involvement of the vermis of the cerebellum in unilateral tinnitus.

Figure 1. Mean pure-tone hearing thresholds for the right and the left ear for the three subject groups.

The solid line represents the hearing thresholds of the control group and the two dashed lines represent the hearing thresholds of the two groups with unilateral tinnitus. The error bars indicate the standard deviation around the mean.

Figure 2. Sound-evoked responses.

Coronal and transversal cross-sections of the human brain in grey-scale with a red-yellow color-coded overlay showing significant responses to sound. The colored areas show a significant response to sound stimuli (omnibus F-test, F>8.34, q<0.05 FDR, pooled over all subjects). Evident from this figure is the auditory pathway, showing the cochlear nuclei (CN; panel A and D), the inferior colliculi (IC; panel A and E), the medial geniculate bodies (MGB; panel B and E) and the auditory cortices (panels A–C and F).

Figure 3. Coronal and sagittal cross-sections of the human brain in grey-scale with a red-yellow color-coded overlay showing voxels in the vermis of the cerebellum that show a significantly larger response to sound in patients compared to controls (t>5.34, p<0.05 FWE).

Figure 4. Region of interest analysis.

The percentage signal changes measured in each ROI of the left and right hemisphere (AAC, PAC, MGB, IC and CN) and the vermis of the cerebellum for both subject groups. The location of each ROI is indicated in yellow on cross-sections of the brain. The responses to the four experimental conditions are shown as box plots for each group separately. For each group, the mean per condition is visualized in the line plot next to the box plots.

Figure 5. Sound lateralization in the auditory pathway.

The lateralization indices for the left hemisphere nuclei (filled symbols) and the right hemisphere nuclei (open symbols) of the auditory pathway (AAC, PAC, MGB, IC and CN) and the cerebellum. A lateralization index of +1 indicates a response to left-ear stimuli only, whereas a value of −1 indicates a response to right-ear stimuli only. The error bars indicate the standard error of the mean. The symbols indicate the two nuclei (†: PAC and ‡: IC) where the difference in lateralization index is significantly different between the two patients and controls.

Figure 6. Connectivity patterns.

Observed functional connectivity patterns in controls (panel A. Controls) and subjects with tinnitus (panel B - Patients). Pearson cross-correlation coefficients were calculated and color-coded based on the value of the coefficient. Panel C. Differences shows the differences in connectivity measures between subject groups for the different ROIs. Significance maps are associated with the observed difference between controls and patients for the Pearson correlation coefficients for each connection. The solid white lines represent homologue auditory nuclei at each level and the white dotted lines indicate the set of connections where on average the connectivity between subcortical and cortical areas is decreased in patients.