Subjective tinnitus is defined as the perception of sound, often described as ringing, hissing, and whistling, in the absence of any external auditory stimuli. Approximately 10% of the general population is estimated to have experienced tinnitus at some point. For the 1% to 3% of patients who experience chronic tinnitus, quality of life is often affected by sleep disturbances, concentration problems, and emotional problems. In Western Europe and the USA, survey data indicate that 13 million people have sought medical advice for their tinnitus. Although the high prevalence of tinnitus makes it an important topic for researchers, the exact mechanisms of action are still unclear, complicating diagnosis and management. Currently, tinnitus is thought to result mainly from abnormal activity in the peripheral auditory system and the limbic system, which is a non-auditory brain area. Eggermont and Roberts proposed that tinnitus might be a perceptual consequence of altered intrinsic neural activity patterns in the central auditory pathway. Such changes in neural activity might damage peripheral auditory structures, thus reducing the afferent input to the central auditory system. In addition, plastic changes in the central auditory system may propagate, resulting in changes in non-auditory brain structures such as the dorsal prefrontal cortex (PFC), anterior cingulate cortex, and the parahippocampal gyrus, which may lead to subsequent emotional problems.[6,7] A recent study found that the associative auditory cortices might play a more important role in the functional attributions of tinnitus than the primary auditory cortex. Tinnitus may increase connectivity in extra-auditory regions such as the brainstem, basal ganglia, cerebellum, and parahippocampal gyrus, as well as the right prefrontal, parietal, and sensorimotor areas. In contrast, decreased connectivity in the right primary auditory cortex, the left PFC, the left fusiform gyrus, and the bilateral occipital regions have also been found in tinnitus patients. Taken together, these data suggest that tinnitus might be associated with modified cortical and subcortical functional connectivity (FC) encompassing intentional, mnemonic, and emotional networks.
Because tinnitus occurs within the resting-brain without any external stimulus, resting-state functional magnetic resonance imaging (rs-fMRI) has been shown to be a useful tool for studying the underlying neural mechanisms.[9–11] Using rs-fMRI data, it is possible to study regional and global changes in brain connectivity characteristics using regional homogeneity and FC methods. Regional homogeneity can be used to measure the degree of similarity of temporal patterns of blood-oxygen-level-dependent signals in a given voxel with those of its nearest neighbors within a single region, and provides crucial information about local synchrony in the brain. In resting-state data, abnormal regional homogeneity is likely to reflect changes in the temporal aspects of spontaneous neural activity. This method has been successfully used to detect local abnormalities in individuals with psychiatric disorders such as attention deficit hyperactivity disorder, depression, Parkinson's disease, Alzheimer's disease, and schizophrenia.[13–19] In addition to regional changes, reports have indicated that tinnitus is associated with emotional problems, with corresponding regional abnormalities that may also lead to changes in inter-regional FC.
Therefore, the aim of this study was to investigate changes in intra- and inter-regional connectivity in individuals with tinnitus. To this end, we used both regional homogeneity and inter-regional FC methods to analyze resting-state fMRI data collected from groups of tinnitus patients and healthy controls.
Participants and methods
The present study protocol was approved by the Institutional Review Board on Experimental Ethics at Sun Yat-sen University, China (approval No. SYSEC-KY-KS-2019-083) (Additional file 1, http://links.lww.com/JR9/A8). Informed consent was obtained from each participant. This study was performed in strict accordance with the Declaration of Helsinki.
The present study was a retrospective study. To avoid the influence of severe hearing loss on rs-fMRI data acquisition, we recruited 17 tinnitus patients (10 men, 7 women, aged 59.5 ± 11.1 years) with normal hearing or mild hearing loss (<40 dB), as well as 20 healthy participants (11 men, 9 women aged 58.2 ± 8.7 years) with normal hearing from Sun Yat-sen Memorial Hospital via advertisement. All hearing abilities were assessed based on pure tone audiometry. The two groups were matched for age and gender, which was confirmed by a chi-square two-sample test. The mean duration of tinnitus in the patient group was 2.7 ± 1.9 years (Table 1). The tinnitus patients underwent rs-MRI scanning at least 12 hours after their last treatment. All participants were right-handed, and the healthy participants were medication-free. Tinnitus was diagnosed according to clinical history, auditory testing, and MRI examinations that excluded other craniocerebral diseases. We carefully measured the dominant tinnitus frequency in each participant. We used the Tinnitus Handicap Inventory (THI) to measure the self-reported severity of the impact of tinnitus.
Magnetic resonance imaging data acquisition
All participants underwent structural and rs-fMRI scanning in a single session conducted with a Philips 3T MRI Achieva scanner (Philips Healthcare, Best, The Netherlands). The head of each participant was positioned within an 8-channel SENSE head coil with sponges to reduce motion artifact.
We conducted structural magnetic resonance imaging using a T1-weighted sagittal three-dimensional coherent gradient echo sequence with the following parameters: repetition time/echo time = 9ms/3.2ms, inversion time = 1035ms, field of view = 256 × 256 × 180 mm3, flip angle = 9°, matrix = 240 × 240, and voxel = 1 × 1 × 1 mm3.
The rs-fMRI sequence was positioned parallel to the anterior commissure-posterior commissure line, and performed with a gradient-echo echo planar imagin planar sequence. Participants were instructed to relax with their eyes closed, not to focus on any specific thoughts, and to avoid falling asleep. rs-fMRI scans were performed with a repetition time/echo time = 2000ms/30ms, field of view = 230 mm × 230 mm, matrix = 64 × 64, slice thickness = 3 mm, interleaved scanning, and flip angle = 90°, SENSE = 2, Ndyn = 240. For each participant, we acquired 33 axial slices without gaps to cover the whole brain. The scan time of the rs-fMRI was approximately 8 minutes.
Image pre-processing was performed as described in our previous work. In brief, the first ten volumes of each scan were discarded to avoid possible instability of the initial MRI signal, resulting in a total of 230 volumes. The images were then corrected for slice-timing and head-motions, normalized to the standard template of the Montreal Neurological Institute (MNI), and re-sampled to 3 × 3 × 3 mm3 cubic voxels. After linear detrending, the data were filtered with a temporal band-pass finite impulse response filter (0.01–0.08 Hz) using MATLAB (Math Work, Natick, MA). Data were excluded if the participant exhibited movement greater than a threshold of 1 mm or if the outlier volumes were greater than 20% of the entire dataset (eg, a change in position of more than 0.75 mm or a change in rotation of more than 1.5°).
Regional homogeneity analysis
We used Kendall coefficient of concordance to compute regional homogeneity for each participant. We used the time series of a given voxel with those of its nearest 26 neighboring voxels in a voxel-wise analysis:
For a given voxel, where rij is the rank of the ith time point in the jth voxel, is the overall mean rank of all neighboring voxels at that time point, n is the number of time points (here n = 230), k represents the number of neighbors within the cluster (including the central voxel, here k = 27), and W ranges from 0 to 1. We created a mask to extract all intracranial voxels, within which all individual Reho maps were divided by their own mean Reho values for standardization purposes. Spatial smoothing of the resulting fMRI data was performed with a Gaussian filter of 6 mm and a full-width half-maximum kernel.
We assessed FC using a seed-based approach with the bilateral inferior frontal gyrus (IFG) and cerebellum as regions of interest, as defined in the automated anatomical labeling atlas. The influence of the nuisance covariants, which included a white matter signal, a cerebrospinal fluid signal, and six motion parameters, was extracted to reflect signal fluctuations of non-neuronal origin. These nuisance covariates, as well as the time series of the ROI, were entered into a General Linear Model to analyze the individual rs-fMRI data for each participant. For normalization purposes, the resulting r-value maps were then transformed into a z value map using Fisher's Z transformation.
Group comparisons of the ReHo analysis were performed using an independent two-sample t-test. Individual maps were averaged within groups and then compared between individuals with tinnitus and healthy controls. For the FC group analysis, a one-sample t test was first used to identify positive and negative FC. These images were then included in a between-groups random effect analysis, which had a 2 × 2 mixed design factorial model (group [control, patient] by hemisphere [right seed, left seed]). To investigate the relationships between FC and clinical symptoms, we used a whole-brain regression analysis with THI scores as covariates of interest. The initial statistical threshold was P < 0.001, and all reported clusters were family-wise error-corrected for multiple comparisons at the cluster level. All coordinates are reported in MNI coordinates, as used by Statistical Parametric Mapping (SPM12; http://www.fil.ion.ucl.ac.uk/spm/software/spm12/).
Regional homogeneity analysis
Compared with control participants, tinnitus patients exhibited significantly (P < 0.05, corrected) increased regional homogeneity in the IFG (MNI: x = 48, y = 12, z = 21, voxels = 290, Z = 3.64, P < 0.05, corrected at a cluster-level) and significantly decreased homogeneity in the anterior lobe of the cerebelleum (MNI: x = −9, y = −60, z = −33, voxels = 807, Z = 4.36, P < 0.05 corrected at the cluster-level) (Fig. 1). In the tinnitus group, we observed a significant negative correlation between THI scores and regional homogeneity in the middle temporal gyrus (MNI: x = 48, y = 3, z = −33, voxels = 50, Z = 4.71, P < 0.05, corrected at the cluster-level) (Fig. 2), but found no significant correlation between THI scores and regional homogeneity in the IFG (Z = 1.684, P = 0.093) or the anterior lobe of the cerebellum (Z = 0.908, P = 0.248).
Inferior frontal gyrus-centered FC analysis
FC analysis based on IFG seed regions revealed between-group differences in the network that contained the auditory and related cortices. Compared with those in the tinnitus group, individuals in the control group showed significantly enhanced FC in the midbrain (MNI: x = 6, y = −18, z = −15, voxels = 42, Z = 3.63, P < 0.05, corrected at the cluster level) and right ventral striatum (MNI: x = 15, y = 9, z = −3, voxels = 8, Z = 3.30, P < 0.05, corrected at the cluster-level) (Fig. 3).
Cerebellum-centered FC analysis
Compared with those in the control group, tinnitus patients showed enhanced FC between the cerebellum and ventromedial PFC (VMPFC) (MNI: x
= 9, y
= 33, z
= −21, voxels = 91, Z
= 3.08, P
< 0.05, corrected at the cluster level), as well as reduced FC between the cerebellum and the left anterior insula (MNI: x
= 45, y
= 12, z = 0, voxels = 34, Z
= 3.16, P
< 0.05, corrected at the cluster-level) (Fig. 4).
In the current study, we used ReHo and FC methods of rs-fMRI data analysis to investigate the differential regional and whole-brain neural connectivity patterns between tinnitus patients and healthy controls. ReHo analysis mainly revealed increased synchronized activities in the IFG and decreased activities in the anterior lobe of the cerebellum. Further analysis indicated a negative correlation between THI scores and ReHo in the middle temporal gyrus. FC analysis mainly revealed differential connectivity patterns between the IFG and the auditory cortex, as well as differential connectivity between the cerebellum and the vMPFC and anterior insula.
The results of the current study are consistent with previous studies. Recent tinnitus research has indicated that tinnitus is related to neuroplastic changes in the central auditory system, as well as in non-auditory brain areas.[21,22] Abnormal neural activity can be identified using the ReHo and FC methods of rs-fMRI data analysis. In previous studies, subjective tinnitus was found to involve abnormal spontaneous neural activity in the central auditory cortex. In the present study, we also found abnormal activities in the middle temporal gyrus, which is located in the auditory cortex. However, we also found changes in regional homogeneity and FC in non-auditory areas of the brain, such as the IFG, the cerebellum, the ventral striatum, and VMPFC. The IFG and VMPFC are located in the frontal lobe, which is implicated in emotional responses, language processing, risk aversion, and memory. The anterior insula is part of the insula cortex, which is enclosed in the frontal, temporal, and parietal lobes, and is involved in emotion processing and consciousness. Meanwhile, the ventral striatum is a major component of the basal ganglia and a vital part of basal ganglia circuitry. It receives and directs input from the cerebral cortex and limbic system. The anterior cerebellar lobe is part of the cerebellum, which is normally considered to play an important role in motor control, as well as cognitive functions that regulate fear and pleasure responses.[25,26] Given the previously established functionality of these brain regions, our results suggest that tinnitus-related brain areas are not only positioned in classic auditory cortices, but may also involve emotion-related regions and additional networks.
Tinnitus and emotion processing
Tinnitus may lead to problems with emotion and attention, for example, anxiety, depression, stress, and insomnia.[27–30] Our current findings suggest that patients with tinnitus could have altered intrinsic brain activity similar to patients with emotional and attention problems. For example, a study on insomnia and regional spontaneous brain activity reported that patients with chronic primary insomnia showed lower regional homogeneity in the bilateral cingulate of the limbic system and right anterior lobe of the cerebellum. In addition, patients with depression were found to have lower FC in the bilateral middle frontal gyrus, brain regions comprising the limbic system (insula, hippocampus, amygdala), and the cerebellum. Our findings that tinnitus patients had lower ReHo in the anterior lobe of the cerebellum and decreased FC between the cerebellum and the anterior insula indicate that tinnitus may be characterized by abnormal brain patterns that are similar to those observed in emotional and attention problems. Thus, emotion-processing brain networks may have interactive relationships with tinnitus.
Interactions between auditory and emotion-related networks in tinnitus
The limbic system has an interactive relationship with the auditory network. Previous studies have suggested that a compromised limbic cortico-striatal circuit leads to compromised evaluation of tinnitus sensation and control of tinnitus perception, thus causing chronic tinnitus. In addition to abnormalities in the frontal brain area, tinnitus patients exhibit a reduction in gray matter volume in the VMPFC. Several studies have proposed a theoretical model for tinnitus stating that the frontal brain area, the ventrolateral PFC, and the dorsolateral PFC could play a significant role in tinnitus generation and perception.[1,35–37]
A hypothesis regarding the canonical cortico-striatal-thalamic circuit (Fig. 5) proposed that the VMPFC has an excitatory influence on the nucleus accumbens. This is consistent with observations of reduced VMPFC functional output in tinnitus patients.[38,39] Decreased VMPFC input to local inhibitory interneurons could result in the disinhibition of NAc, which could lead to higher NAc activity. This altered NAc-VMPFC interaction may also contribute to aberrant auditory activity (ie, tinnitus) by entering the limbic system via the amygdala. Our present finding of enhanced FC between the IFG and the midbrain and ventral striatum supports the cortico-striatal circuit hypothesis of tinnitus.
In addition to the IFG, the paraflocculus, which is part of the cerebellum, may also play an important role in tinnitus. It may act not only as a generator but also as a gating zone that reduces tinnitus. The paraflocculus was found to have elevated neural activity in rats with psychophysical evidence of tinnitus, which suggested that slow plastic changes in the cerebellum may underlie chronic tinnitus, and further, may be one of the generators of tinnitus. In the rat model, sodium salicylate was used to induce alterations in the paraflocculus. This treatment can also modulate activity in the auditory cortex. Therefore, sodium salicylate may represent a potential treatment option for tinnitus.
Treatment of tinnitus
Based on the results of the current study, tinnitus treatment could be divided into auditory-based treatment and non-audiology treatment, such as emotional therapy and cognitive behavioral therapy. In terms of auditory treatment, repetitive transcranial magnetic stimulation of the auditory cortex has been found to effectively induce certain lasting effects associated with tinnitus relief. In addition, a previous study showed that a combination of high frequency repetitive transcranial magnetic stimulation of the PFC and low-frequency stimulation of the temporal cortex had an enhanced treatment effect in tinnitus patients. Cochlear implants and other surgical interventions have also been found to be effective in reducing tinnitus symptoms.
For emotional treatments for tinnitus, transcranial direct current stimulation has been found to be useful in modulating anxiety. Further, intensive sound masking therapy was found to lower the THI score in patients with tinnitus. Other options include cognitive behavioral therapy and retraining therapy, which can be components of a daily therapeutic routine.[47–49] In addition, the Mindfulness-Based Stress Reduction program was found to increase FC in the attention network and decrease depression. Furthermore, active music therapy (Heidelberg model) has been found to be useful in improving the Goebel-Hiller (TQ) score. This, as well as other music therapies (eg, passive music therapy) could also be beneficial in relieving tinnitus symptoms.
Limitations and further study
The sample size of this study was relatively small (n = 17 patients), which could affect the significance of the correlation between regional homogeneity in the IFG and that in the THI. Therefore, future research with larger sample sizes should investigate neural brain patterns with a focus on either homogeneous tinnitus or specific tinnitus characteristics (such as localization, intensity, duration, type of sound, and treatment response).
Our data indicate that tinnitus is associated with abnormal regional homogeneity and FC in the auditory-limbic-cerebellum network, and highlight the key role of non-auditory brain structures in the etiology of tinnitus. We propose that treatment of tinnitus should consider both auditory and non-auditory systems to enhance treatment effects, and thus increase the quality of life of patients with tinnitus.
HY, HL, HX, and YZ conceived and designed the study, interpreted and analyzed the data, and wrote the manuscript. XL conceived and designed the study, interpreted and analyzed the data, and approved the final manuscript. XZ designed and performed the study, interpreted and analyzed the data, and wrote the manuscript.
This study was supported by the National Natural Science Foundation of China (No. 81170921) to YZ.
Institutional review board statement
The present study protocol was approved by the Institutional Review Board on Experimental Ethics at Sun Yat-sen University, China (approval No. SYSEC-KY-KS-2019-083).
Declaration of patient consent
The authors certify that they have obtained the patient consent forms. In the forms, patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity.
Conflicts of interest
The authors declare no conflicts of interest.
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