Investigating the Causative Effects of Tinnitus of Different Severity and Stages on the White Matter Microstructural Integrity

ABSTRACT There is increasing evidence that white matter fibres play an important role in tinnitus. A directed bilateral Mendelian randomization (MR) analysis based on genome‐wide association studies (GWAS) has been implemented to explore the impact of idiopathic tinnitus on the brain white matter (WM) integrity of different severity and stages at a causal level. The tinnitus‐related GWAS is derived from the research of 117,882 European participants, which contains accounts of tinnitus at different severities and stages. WM diffusion indices, which come from GWAS of 3144 brain imaging phenotypes from the UK Biobank, based on tract‐based spatial statistics and neurite orientation dispersion and density imaging, represent its integrity in this study. The primary estimate was inverse‐variance weighted, with heterogeneity and pleiotropy detected using MR Pleiotropy Residual Sum and Outlier and MR‐Egger. This study revealed a significant causal relationship between tinnitus and brain WM microstructural alterations, including changes primarily within the thalamic and acoustic radiation, limbic‐related fibre bundles, as well as fibres along the transmission pathways of auditory information from peripheral to central. Interestingly, we found that individuals exhibiting WM changes in the internal capsule, corticospinal tract and tapetum might have previously experienced tinnitus. Furthermore, moderate tinnitus patients exhibit the most pronounced WM integrity changes. This study substantiates that tinnitus can instigate substantial WM microstructural alterations mainly within the auditory‐thalamic‐limbic system and the auditory information transmission pathway from peripheral to central, while the reciprocal causality is not supported. Moreover, the data underscores that WM integrity changes vary depending on the severity and stages, and moderate tinnitus precipitates the most significant. Alterations in several specific WM fibre bundles indicate a history of tinnitus.