Longitudinal Resting-State fMRI Reveals Temporal Evolution of Network-Level Alterations in a Mouse Model of Tinnitus

Tinnitus, one of the most common hearing disorders, profoundly impacts patients’ quality of life, often leading to severe emotional distress and sleep disturbances. Despite its clinical burden, therapeutic options remain limited due to an incomplete understanding of its pathophysiology. While cochlear damage is a known trigger, accumulating evidence suggests that maladaptive central plasticity—particularly in non-auditory networks—plays a central role in the chronicity of tinnitus. Specifically, limbic structures (hippocampus, amygdala) and striatal regions (caudate putamen) show altered functional connectivity with auditory nuclei in both human fMRI and animal models. To systematically map these network-level changes, we employed a noise-induced tinnitus mouse model and performed longitudinal resting-state BOLD fMRI across 27 brain regions of interest (ROIs). Our multi-time point analysis revealed early phase hyperactivity (days 1 and 7 post-injury) in auditory thalamocortical pathways, consistent with compensatory gamma oscillation mechanisms. This was followed by delayed limbic-striatal engagement (day 28), characterized by enhanced hippocampal-amygdala connectivity and caudate putamen dysregulation, which aligns with human studies of tinnitus-related emotional processing. We observed a dynamic network expansion over time, where initially localized auditory abnormalities progressively recruited the default mode and salience networks. These findings validate the ‘central gain reorganization’ hypothesis and highlight novel therapeutic targets. Notably, the caudate putamen emerged as a key modulator in the gating of phantom sound perception, suggesting the potential efficacy of striatal-directed neuromodulation. This work bridges translational gaps by demonstrating that tinnitus is a whole-brain disorder requiring network-level interventions, paving the way for personalized neuromodulatory strategies.