Punit Makani

Tinnitus is characterized by a persistent ringing or buzzing in the ears, occurring without any external sound stimuli. It significantly affects quality of life, leading to issues such as impaired concentration, sleep disturbances, and often results in psychological challenges like anxiety and depression. Tinnitus commonly co-occurs with other auditory conditions, particularly hearing loss and/or hyperacusis. About 90% of individuals with tinnitus have reported some degree of hearing loss, while up to 10 % of individuals with tinnitus have reported normal hearing. Additionally, hyperacusis, an increased sensitivity to normal sound levels, is prevalent in about 63% of individuals with tinnitus. Neuroimaging offers a unique possibility to explore both structural and functional characteristics in the brain of individuals with tinnitus, hearing loss, and hyperacusis. While earlier studies, especially structural neuroimaging studies, have highlighted some brain alterations linked to tinnitus, the findings have been largely inconsistent and heterogeneous. This inconsistency has been attributed to factors such as small sample sizes and the heterogeneity within tinnitus populations, including variations in the presence or absence of hearing loss and/or hyperacusis. This thesis aims to untangle the complex interaction between tinnitus, hearing loss, and hyperacusis using a larger and more representative sample, addressing factors that have been suggested to contribute to the inconsistent and heterogeneous findings reported in previous studies. In chapter 2, a meta-analysis was conducted comparing four groups: 1) individuals with normal hearing and tinnitus, 2) individuals with normal hearing, 3) individuals with hearing loss and tinnitus, and 4) individuals with hearing loss. In the normal hearing groups, tinnitus was associated with smaller gray matter volumes in the inferior temporal gyrus, whereas among the hearing loss groups, tinnitus was linked to higher gray matter volumes in the lingual gyrus and the precuneus. Consequently, these findings provide an explanation for the heterogeneous results in earlier studies and led to conclude that the presence or absence of hearing loss plays a critical role in brain structural differences in individuals with tinnitus. In chapter 3, a retrospective case-control study was conducted to investigate the interaction between tinnitus and hearing loss on structural gray matter volumes comparing four groups: 1) individuals with normal hearing and tinnitus, 2) individuals with normal hearing, 3) individuals with hearing loss and tinnitus, and 4) individuals with hearing loss. A significant interaction was found between the effects of tinnitus and hearing loss on several gray matter brain structures. Consistent with the meta-analysis, the results indicated that in the normal hearing groups, tinnitus was associated with smaller gray matter volumes in Heschl’s gyrus, the posterior insula, the ventromedial prefrontal cortex, the middle cingulate cortex, the supplementary motor area, and the inferior frontal gyrus. In sharp contrast, in the hearing loss groups, tinnitus was linked to higher gray matter volumes in Heschl’s gyrus, the posterior insula, the lingual gyrus, the parahippocampal region, the ventromedial prefrontal cortex, and the inferior frontal gyrus. This study highlighted the distinction between the structural abnormalities associated with tinnitus in normal hearing and those linked to tinnitus in hearing loss, which led to conclude that there are potentially unique mechanisms of tinnitus in normal hearing compared to those in hearing loss. In chapter 4, a retrospective case-control study was conducted to investigate gray matter differences associated with hyperacusis by comparing two groups of individuals with tinnitus and hearing loss: 1) those who scored above the threshold for hyperacusis based on the validated hyperacusis questionnaire, and 2) those who scored below the threshold for hyperacusis. The findings indicated that hyperacusis was associated with smaller gray matter volumes in the supplementary motor area (part of the motor region). Additionally, using the gray matter volumes of the supplementary motor area, individuals with hyperacusis were classified with an accuracy of 80% in area-under-the-curve analysis. Chapter 5 describes similar results in subjects without hearing loss confirm a reduction of white matter in the supplementary motor cortex associated with hyperacusis. Previous studies by other research groups have found hyperacusis to be associated with central gain within the auditory pathway. The studies in Chapter 4 and 5 were the first to demonstrate that non-auditory regions, such as the motor region, were also impacted in hyperacusis. It led to conclude that differences in the motor region in hyperacusis might be associated with motor behavior, potentially related to hyperactive and avoidance behaviors in response to loud sound stimuli. It further led to the hypothesis that the supplementary motor area could serve as a structural biomarker to identify hyperacusis in individuals with tinnitus, regardless of hearing levels. While the findings presented in this thesis advance understanding of the complex interaction between tinnitus, hearing loss, and hyperacusis, particularly with respect to underlying structural mechanisms, further research is required to strengthen their validity and clinical relevance. A promising direction for future studies is the use of pre- and post-treatment measurements in individuals undergoing targeted interventions, such as cognitive behavioral therapy for tinnitus or audiological treatment for hyperacusis. Combining structural and functional neuroimaging with behavioral and physiological measures pre- and post-treatment may also help identify objective biomarkers associated with symptom change, thereby improving mechanistic insight, and supporting the development of reliable biomarkers for tinnitus and hyperacusis. Finally, longitudinal designs are essential, particularly large-scale population cohorts that can assess structural and functional brain differences associated with the onset of tinnitus and hyperacusis, as well as with their chronification.