Neural hyperactivity in tinnitus patients
During fMRI scans, auditory stimuli of several frequencies were presented: one matched in frequency to each patient’s tinnitus (TF-matched; see Methods), and others within 2 octaves above or below the TF-matched stimulus. In this way, each tinnitus patient, and their “stimulus-matched” control participant, heard a custom set of stimuli based on the frequency of the patient’s tinnitus sensation (Suppl. Table 1
). We thus compared levels of stimulus-evoked function in individuals with and without tinnitus ().
When presented with TF-matched stimuli, tinnitus patients demonstrated higher fMRI signal than controls in the ventral striatum, specifically the nucleus accumbens (NAc; p(corr) < 0.05, ). Though a similar trend was present for all stimulus frequencies in separate ROI analyses, these differences were not significant (p(corr) > 0.05, Bonferroni-corrected for the number of tests performed, i.e., 5). Thus, NAc hyperactivity in tinnitus patients appeared to be specific for the tinnitus frequency. Examining pairwise correlations between NAc activity and age or hearing loss clearly shows that these variables had no effect on group differences in fMRI signal (). Indeed, NAc hyperactivity in tinnitus patients was present in the single-voxel analysis (), in which hearing loss was a “nuisance” covariate, as well as in a separate ROI analysis, in which age was a covariate: t(20) = 5.34, p = 0.00004. Additionally, NAc hyperactivity persisted in an ROI analysis restricted to the four youngest patients (t(13) = 4.98, p = 0.0003), where age and hearing loss were equivalent between groups (age: t(13) = 0.99, p = 0.34; mean hearing loss: t(13) = 0.64, p = 0.53).
Figure 1 Hyperactivity in tinnitus patients was localized to the ventral striatum near the nucleus accumbens (center of gravity: X,Y,Z = −16, 6, −0.5; volume = 108 mm3). A. Voxels exhibiting significant (p(corr) < 0.05) between-groups differences (more ...)
In an analysis restricted to voxels within the auditory cortex and medial geniculate nuclei (MGN; a “masked analysis”, as defined in Methods), tinnitus patients exhibited greater fMRI signal than controls in bilateral posterior superior temporal gyri and sulci (p
< 0.01, k > 108 mm3
). Hyperactivity in posterior superior temporal cortex (pSTC) was significant at the single-voxel level for all stimulus frequencies except the lowest (, t
). However, in an ROI comprised of voxels exhibiting significant between-groups differences for any stimulus frequency (), a similar trend was observed for the lowest stimulus frequencies ((20)
= 2.49, p
= 0.02). Tinnitus patients also demonstrated increased signal in response to TF-matched stimuli in left medial Heschl’s gyrus (mHG, , ) at the single-voxel level. This hyperactivity in mHG, the likely location of primary auditory cortex (Penhune et al., 1996
; Rademacher et al., 2001
), was not significant for other stimulus conditions (). Again, mean hearing loss (a “nuisance” covariate in the above analyses) and age did not affect these results; an additional ROI analysis restricted to the four youngest patients yielded hyperactivity for TF-matched stimuli (pSTC: t(13)
= 4.05, p
= 0.001; mHG: t(13)
= 3.37, p
= 0.005). In addition, hyperactivity in mHG was still apparent when comparing fMRI signal in tinnitus patients on TF-matched trials against fMRI signal in controls on all stimulus trials (ROI analysis, t(20)
= 2.11, p
= 0.048). No differences in fMRI signal were seen between groups in any MGN voxels at any stimulus frequency.
Masked fMRI analysis of auditory cortex and MGN
Figure 2 In a masked analysis restricted to auditory cortex and thalamus, hyperactivity in tinnitus patients was demonstrated in auditory cortex. A. Voxels that demonstrated between-groups differences in fMRI signal (p < 0.01, k > 108 mm3) are (more ...)
Anatomical anomalies in the brains of tinnitus patients
In VBM analyses, significant differences in anatomical images were seen between groups in the subcallosal region, in ventromedial prefrontal cortex (vmPFC; t > 4.65 p < 0.0001, ). For both modulated and unmodulated grey matter (GM) images (interpreted as GM amount and concentration, respectively), tinnitus patients exhibited significantly reduced signal intensity (). Tinnitus patients demonstrated a corresponding increase in vmPFC signal intensity in unmodulated white matter (WM) images as well (), which can be interpreted as an increase in WM concentration in this region relative to other types of tissue.
Figure 3 Structural differences between tinnitus patients and control participants were identified in ventromedial prefrontal cortex (vmPFC). A. Voxels demonstrating significant differences in VBM values between groups are shown on group-averaged anatomical images. (more ...)
These effects appear to be independent of age and total GM or WM volume; these factors were used as covariates in all VBM analyses. Additionally, these between-groups differences persisted when mean hearing loss was entered as a covariate in ROI analyses as well (GM amount: t = 4.70, p < 0.0001; GM concentration: t = 5.76, p < 0.00001; WM concentration: t = 7.14, p < 0.00001). Thus, anatomical differences were not related to measurable hearing loss. Examination of pairwise scatterplots of anatomical effects and age or hearing loss () shows little relationship between group differences in VBM measures and these variables, and additional ROI analyses comparing the youngest patients and control participants yield similar results (GM amount, patients < controls: t(13) = 4.84, p = 0.0003; GM concentration, patients < controls: t(13) = 4.68, p = 0.0004; WM concentration, patients > controls: t(13) = 4.97, p = 0.0003).
In a masked analysis restricted to voxels within auditory-sensory regions, including auditory cortex, MGN, and IC, no significant differences were found between tinnitus patients and controls (p > 0.01).
Structure-function correspondence in tinnitus-related regions
In a masked VBM analysis restricted to NAc voxels that demonstrated a significant functional difference between participant groups, there was no significant corresponding anatomical difference (p > 0.01). Similarly, in a masked fMRI analysis restricted to vmPFC voxels that demonstrated significant anatomical between-groups differences, we saw no significant functional difference between tinnitus patients and controls (p > 0.01). So, no single brain region exhibited both structural and functional differences.
There was, however, a correlation between NAc fMRI signal and vmPFC VBM values in tinnitus patients (r = 0.73, t(8) = 2.99, p = 0.02; outlier removed, see Methods), such that patients with the highest degree of NAc hyperactivity also had correspondingly greater anatomical differences (i.e., decreases in GM concentration and amount, with increased WM amount compared to controls; ). This relationship was not present in control participants (r = −0.03, t(9) = −0.10, p = 0.919). Moreover, there was moderate correspondence between limbic abnormalities and primary auditory cortex hyperactivity in tinnitus patients (NAc × mHG: r = 0.51, t(8) = 1.67, p = 0.13, ; vmPFC × mHG: r = 0.61, t(8) = 2.17, p = 0.06, ). Correlations between limbic and posterior auditory areas were not significant (NAc × pSTC; r = 0.17, t(8) = 0.49, p = 0.64, ; vmPFC × pSTC: r = 0.42, t(8) = 1.30, p = 0.23, ), nor was activity in primary and posterior auditory cortex related (mHG × pSTC: r = −0.13, t(8) = 0.38, p = 0.72, ). This suggests that the degree of functional and structural differences in the limbic system (i.e., NAc and vmPFC, respectively) and primary auditory cortex may be directly related in tinnitus patients.
Figure 4 Correlations between functional and anatomical markers are displayed. Data corresponding to NAc, mHG, and pSTC reflect fMRI signal during TF-matched trials. Global VBM values in vmPFC reflect the mean difference in modulated and unmodulated grey matter (more ...)