An Inverse Relationship Between Gray Matter Volume and Speech-in-Noise Performance in Tinnitus Patients with Normal Hearing Sensitivity.

Speech-in-noise (SiN) recognition difficulties are often reported in patients with tinnitus. Although brain structural changes such as reduced gray matter (GM) volume in auditory and cognitive processing regions have been reported in the tinnitus population, it remains unclear how such changes influence speech understanding, such as SiN performance. In this study, pure-tone audiometry and Quick Speech-in-Noise test were conducted on individuals with tinnitus and normal hearing and hearing-matched controls. T1-weighted structural MRI images were obtained from all participants. After preprocessing, GM volumes were compared between tinnitus and control groups using whole-brain and region-of-interest analyses. Further, regression analyses were performed to examine the correlation between regional GM volume and SiN scores in each group. The results showed decreased GM volume in the right inferior frontal gyrus in the tinnitus group relative to the control group. In the tinnitus group, SiN performance showed a negative correlation with GM volume in the left cerebellum (Crus I/II) and the left superior temporal gyrus; no significant correlation between SiN performance and regional GM volume was found in the control group. Even with clinically defined normal hearing and comparable SiN performance relative to controls, tinnitus appears to change the association between SiN recognition and regional GM volume. This change may reflect compensatory mechanisms utilized by individuals with tinnitus who maintain behavioral performance.

A large-scale diffusion imaging study of tinnitus and hearing loss.

Subjective, chronic tinnitus, the perception of sound in the absence of an external source, commonly occurs with many comorbidities, making it a difficult condition to study. Hearing loss, often believed to be the driver for tinnitus, is perhaps one of the most significant comorbidities. In the present study, white matter correlates of tinnitus and hearing loss were examined. Diffusion imaging data were collected from 96 participants-43 with tinnitus and hearing loss (TINHL), 17 with tinnitus and normal hearing thresholds (TINNH), 17 controls with hearing loss (CONHL) and 19 controls with normal hearing (CONNH). Fractional anisotropy (FA), mean diffusivity and probabilistic tractography analyses were conducted on the diffusion imaging data. Analyses revealed differences in FA and structural connectivity specific to tinnitus, hearing loss, and both conditions when comorbid, suggesting the existence of tinnitus-specific neural networks. These findings also suggest that age plays an important role in neural plasticity, and thus may account for some of the variability of results in the literature. However, this effect is not seen in tractography results, where a sensitivity analysis revealed that age did not impact measures of network integration or segregation. Based on these results and previously reported findings, we propose an updated model of tinnitus, wherein the internal capsule and corpus callosum play important roles in the evaluation of, and neural plasticity in response to tinnitus.

Salience, emotion, and attention: The neural networks underlying tinnitus distress revealed using music and rest.

In the present study, we used an innovative music-rest interleaved fMRI paradigm to investigate the neural correlates of tinnitus distress. Tinnitus is a poorly-understood hearing disorder where individuals perceive sounds, in the absence of an external source. Although the great majority of individuals habituate to chronic tinnitus and report few symptoms, a minority report debilitating distress and annoyance. Prior research suggests that a diverse set of brain regions, including the attention, the salience, and the limbic networks, play key roles in mediating both the perception of tinnitus and its impact on the individual; however, evidence of the degree and extent of their involvement has been inconsistent. Here, we minimally modified the conventional resting state fMRI by interleaving it with segments of jazz music. We found that the functional connectivity between a set of brain regions-including cerebellum, precuneus, superior/middle frontal gyrus, and primary visual cortex-and seeds in the dorsal attention network, the salience network, and the amygdala, were effective in fractionating the tinnitus patients into two subgroups, characterized by the severity of tinnitus-related distress. Further, our findings revealed cross-modal modulation of the attention and salience networks by the visual modality during the music segments. On average, the more bothersome the reported tinnitus, the stronger was the exhibited inter-network functional connectivity. This study substantiates the essential role of the attention, salience, and limbic networks in tinnitus habituation, and suggests modulation of the attention and salience networks across the auditory and visual modalities as a possible compensatory mechanism for bothersome tinnitus.

Decreased resting perfusion in precuneus and posterior cingulate cortex predicts tinnitus severity.

Functional magnetic resonance imaging has been increasingly used to understand the mechanisms involved in subjective tinnitus; however, researchers have struggled to reach a consensus about a primary mechanistic model to explain tinnitus. While many studies have used functional connectivity of the BOLD signal to understand how patterns of activity change with tinnitus severity, there is much less research on whether there are differences in more fundamental physiology, including cerebral blood flow, which may help inform the BOLD measures. Here, arterial spin labeling was used to measure perfusion in four regions-of-interest, guided by current models of tinnitus, in a sample of 60 tinnitus patients and 31 control subjects. We found global reductions in cerebral perfusion in tinnitus compared with controls. Additionally, we observed a significant negative correlation between tinnitus severity and perfusion. These results demonstrate that examining perfusion from the whole brain may present a complementary tool for studying tinnitus. More research will help better understand the physiology underlying these differences in perfusion.

Replicability of Neural and Behavioral Measures of Tinnitus Handicap in Civilian and Military Populations: Preliminary Results.

Purpose In the past decade, resting-state functional connectivity, acquired using functional magnetic resonance imaging (fMRI), has emerged as a popular measure of tinnitus, especially as related to self-reported handicap or psychological reaction. The goal of this study was to assess replicability of neural correlates of tinnitus, namely, resting-state functional connectivity, in the same individuals acquired over 2 sessions. Method Data were collected at 2 different sites (University of Illinois at Urbana-Champaign and Joint Base San Antonio Wilford Hall Ambulatory Surgical Center) using similar 3T magnets and similar data acquisition paradigms. Thirty-six patients (all civilians) were scanned using resting-state fMRI at the University of Illinois at Urbana-Champaign. Ten patients, active-duty Service members and Veterans, were scanned at the Wilford Hall Ambulatory Surgical Center and the Department of Defense Hearing Center of Excellence. Each participant was scanned twice, a week apart, using identical protocols of 10 min resting-state fMRI. Results Tinnitus handicap scores using the Tinnitus Functional Index and the Tinnitus Primary Function Questionnaire ranged between no or mild handicap to moderately severe handicap but did not significantly differ between visits. We examined the default mode, dorsal attention, and auditory resting-state networks and found that the strength of the within-network functional connections across visit was similar for the attention and default mode networks but not for the auditory network. In addition, the functional connection between the attention network and precuneus, a region of the default mode network, was also replicable across visits. Conclusions Our results show that resting-state fMRI measures are replicable and reliable in patients with a subjective condition, although some networks and functional connections may be more stable than others. This paves the way for using resting-state fMRI to measure the efficacy of tinnitus interventions and as a tool to help propose better management options.

Dissociating tinnitus patients from healthy controls using resting-state cyclicity analysis and clustering.

Chronic tinnitus is a common and sometimes debilitating condition that lacks scientific consensus on physiological models of how the condition arises as well as any known cure. In this study, we applied a novel cyclicity analysis, which studies patterns of leader-follower relationships between two signals, to resting-state functional magnetic resonance imaging (rs-fMRI) data of brain regions acquired from subjects with and without tinnitus. Using the output from the cyclicity analysis, we were able to differentiate between these two groups with 58-67% accuracy by using a partial least squares discriminant analysis. Stability testing yielded a 70% classification accuracy for identifying individual subjects' data across sessions 1 week apart. Additional analysis revealed that the pairs of brain regions that contributed most to the dissociation between tinnitus and controls were those connected to the amygdala. In the controls, there were consistent temporal patterns across frontal, parietal, and limbic regions and amygdalar activity, whereas in tinnitus subjects, this pattern was much more variable. Our findings demonstrate a proof-of-principle for the use of cyclicity analysis of rs-fMRI data to better understand functional brain connectivity and to use it as a tool for the differentiation of patients and controls who may differ on specific traits.

Changes in gray and white matter in subgroups within the tinnitus population.

In this study, we investigated gray and white matter changes in subgroups within the larger tinnitus population related to differences in severity or duration of tinnitus symptoms. Tinnitus is the illusory perception of sound in the absence of an external source, most often experienced as a chronic condition. The psychological reaction to the sound constitutes the severity, or degree of discomfort experienced, and the duration refers to the time since onset of chronic tinnitus. We used voxel- and surface-based morphometry to investigate gray matter changes and diffusion tensor imaging (using fractional anisotropy, or FA, metrics) to assess changes in orientation of white matter tracts, using both whole brain and region of interest analyses. Whole brain analyses revealed decreased cortical thickness in the left parahippocampal gyrus in those with more severe tinnitus compared to a group with a milder reaction, and reduced gray matter volume in left anterior cingulate in those with mild tinnitus compared to a normal hearing control group without tinnitus. In the analysis based on FA, no significant differences were revealed between the subgroups or with respect to control groups in either whole brain or region of interest analyses. Our results suggest that these subgroups within the tinnitus population likely exhibit different anatomical alterations related to the disorder, which may explain the variable findings in the literature, particularly in terms of gray matter.

Connectivity of precuneus to the default mode and dorsal attention networks: A possible invariant marker of long-term tinnitus.

Resting state functional connectivity studies of tinnitus have provided inconsistent evidence concerning its neural bases. This may be due to differences in the methodology used, but it is also likely related to the heterogeneity of the tinnitus population. In this study, our goal was to identify resting state functional connectivity alterations that consistently appear across tinnitus subgroups. We examined two sources of variability in the subgroups: tinnitus severity and the length of time a person has had chronic tinnitus (referred to as tinnitus duration). Data for the current large-scale analysis of variance originated partly from our earlier investigations (Schmidt et al., 2013; Carpenter-Thompson et al., 2015) and partly from previously unpublished studies. Decreased correlations between seed regions in the default mode network and the precuneus were consistent across individuals with long-term tinnitus (who have had tinnitus for greater than one year), with more bothersome tinnitus demonstrating stronger decreases. In the dorsal attention network, patients with moderately severe tinnitus showed increased correlations between seeds in the network and the precuneus, with this effect also present in only some patients with mild tinnitus. The same effects were not seen in patients with mild tinnitus and tinnitus duration between 6 and 12 months. Our results are promising initial steps towards identifying invariant neural correlates of tinnitus and indexing differences between subgroups.

Neural Plasticity of Mild Tinnitus: An fMRI Investigation Comparing Those Recently Diagnosed with Tinnitus to Those That Had Tinnitus for a Long Period of Time.

Objectives. The aim of the study was to compare differences in neural correlates of tinnitus in adults with recent onset and others who had the disorder for longer than a year. Design. A total of 25 individuals with tinnitus were divided into groups based on the amount of time for which they had experienced tinnitus: <1 year (RTIN) or >1 year (LTIN). Subjects underwent an fMRI scan while listening to affective sounds from the International Affective Digital Sounds database. Resting state functional connectivity data were also collected. Results. The RTIN group recruited the posterior cingulate and insula to a greater extent than the LTIN group when processing affective sounds. In addition, we found that the LTIN group engaged more frontal regions when listening to the stimuli compared to the RTIN group. Lastly, we found increased correlations between the default mode network and the precuneus in RTIN patients compared to LTIN at rest. Conclusion. Our results suggest that the posterior cingulate and insula may be associated with an early emotional reaction to tinnitus in both task and resting states. Over time, tinnitus patients may recruit more frontal regions to better control their emotional response and exhibit altered connectivity in the default mode network.

Alterations to the attention system in adults with tinnitus are modality specific.

Generation and persistence of tinnitus following hearing loss may be due to aberrant engagement of attention. Here, functional MRI was used to determine differences in auditory and visual attention processing in adults with tinnitus and hearing loss compared to two age-matched control groups, one with matched hearing loss and the other with normal hearing thresholds. Attentional processing was investigated using a short-term memory task with varying loads, employing unfamiliar Korean letters in the visual condition and non-speech sounds in the auditory condition. We found similar behavioral response across the three groups for both modalities and tasks. For the auditory modality, the response of the attention network was suppressed in the tinnitus group compared to the control groups for both task loads, with the effect being more pronounced at high load. In contrast, in the visual modality, the tinnitus group exhibited greater response of the attention network, regardless of memory load, compared to the control groups. The results increase our understanding of the neural mechanisms of tinnitus and suggest that interventions that manipulate attention, especially in the visual domain, should be further investigated.

Alterations of the emotional processing system may underlie preserved rapid reaction time in tinnitus.

Although alterations of the limbic system have been linked to tinnitus persistence, the neural networks underlying such alteration are unclear. The present study investigated the effect of tinnitus on emotional processing in middle-aged adults using functional magnetic resonance imaging and stimuli from the International Affective Digital Sounds database. There were three groups of participants: bilateral hearing loss with tinnitus (TIN), age- and gender-matched controls with bilateral hearing loss without tinnitus (HL) and matched normal hearing controls without tinnitus (NH). In the scanner, subjects rated sounds as pleasant, unpleasant, or neutral. The TIN and NH groups, but not the HL group, responded faster to affective sounds compared to neutral sounds. The TIN group had elevated response in bilateral parahippocampus and right insula compared to the NH group, and left parahippocampus compared to HL controls for pleasant relative to neutral sounds. A region-of-interest analysis detected increased activation for NH controls in the right amygdala when responding to affective stimuli, but failed to find a similar heightened response in the TIN and HL groups. All three groups showed increased response in auditory cortices for the affective relative to neutral sounds comparisons. Our results suggest that the emotional processing network is altered in tinnitus to rely on the parahippocampus and insula, rather than the amygdala, and this alteration may maintain a select advantage for the rapid processing of affective stimuli despite the hearing loss. The complex interaction of tinnitus and the limbic system should be accounted for in development of new tinnitus management strategies.

The effect of mild-to-moderate hearing loss on auditory and emotion processing networks.

We investigated the impact of hearing loss (HL) on emotional processing using task- and rest-based functional magnetic resonance imaging. Two age-matched groups of middle-aged participants were recruited: one with bilateral high-frequency HL and a control group with normal hearing (NH). During the task-based portion of the experiment, participants were instructed to rate affective stimuli from the International Affective Digital Sounds (IADS) database as pleasant, unpleasant, or neutral. In the resting state experiment, participants were told to fixate on a "+" sign on a screen for 5 min. The results of both the task-based and resting state studies suggest that NH and HL patients differ in their emotional response. Specifically, in the task-based study, we found slower response to affective but not neutral sounds by the HL group compared to the NH group. This was reflected in the brain activation patterns, with the NH group employing the expected limbic and auditory regions including the left amygdala, left parahippocampus, right middle temporal gyrus and left superior temporal gyrus to a greater extent in processing affective stimuli when compared to the HL group. In the resting state study, we observed no significant differences in connectivity of the auditory network between the groups. In the dorsal attention network (DAN), HL patients exhibited decreased connectivity between seed regions and left insula and left postcentral gyrus compared to controls. The default mode network (DMN) was also altered, showing increased connectivity between seeds and left middle frontal gyrus in the HL group. Further targeted analysis revealed increased intrinsic connectivity between the right middle temporal gyrus and the right precentral gyrus. The results from both studies suggest neuronal reorganization as a consequence of HL, most notably in networks responding to emotional sounds.

Using resting state functional connectivity to unravel networks of tinnitus.

Resting state functional connectivity (rs-fc) using fMRI has become an important tool in examining differences in brain activity between patient and healthy populations. Studies employing rs-fc have successfully identified altered intrinsic neural networks in many neurological and psychiatric disorders, including Alzheimer's disease, schizophrenia, and more recently, tinnitus. The neural mechanisms of subjective tinnitus, defined as the perception of sound without an external source, are not well understood. Several inherent networks have been implicated in tinnitus; these include default mode, auditory, dorsal attention, and visual resting-state networks. Evidence from several studies has begun to suggest that tinnitus causes consistent modifications to these networks, including greater connectivity between limbic areas and cortical networks not traditionally involved with emotion processing, and increased connectivity between attention and auditory processing brain regions. Such consistent changes to these networks may allow for the identification of objective brain imaging measures of tinnitus, leading to a better understanding of the neural basis of the disorder. Further, examination of rs-fc allows us to correlate behavioral measures, such as tinnitus severity and comorbid factors including hearing loss, with specific intrinsic networks. This article is part of a Special Issue entitled Human Auditory Neuroimaging.

Default mode, dorsal attention and auditory resting state networks exhibit differential functional connectivity in tinnitus and hearing loss.

We investigated auditory, dorsal attention, and default mode networks in adults with tinnitus and hearing loss in a resting state functional connectivity study. Data were obtained using continuous functional magnetic resonance imaging (fMRI) while the participants were at "rest" and were not performing any task. Participants belonged to one of three groups: middle-aged adults with tinnitus and mild-to-moderate high frequency hearing loss (TIN), age-matched controls with normal hearing and no tinnitus (NH), and a second control group with mild-to-moderate high frequency hearing loss without tinnitus (HL). After standard preprocessing, (a) a group independent component analysis (ICA) using 30 components and (b) a seeding-based connectivity analysis were conducted. In the group ICA, the default mode network was the only network to display visual differences between subject groups. In the seeding analysis, we found increased connectivity between the left parahippocampus and the auditory resting state network in the TIN group when compared to NH controls. Similarly, there was also an increased correlation between the right parahippocampus and the dorsal attention network when compared to HL controls. Other group differences in this attention network included decreased correlations between the seed regions and the right supramarginal gyrus in TIN patients when compared to HL controls. In the default mode network, there was a strong decrease in correlation between the seed regions and the precuneus when compared to both control groups. The findings of this study identify specific alterations in the connectivity of the default mode, dorsal attention, and auditory resting state networks due to tinnitus. The results suggest that therapies for tinnitus that mitigate the increased connectivity of limbic regions with auditory and attention resting state networks and the decreased coherence of the default mode network could be effective at reducing tinnitus-related distress.