Direct evidence for synaptic density changes in tinnitus: ¹⁸F-SynVesT-1 PET reveals novel targets beyond metabolic changes.

Abstract

While ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET supports increased neuronal activity in tinnitus, synaptic density abnormalities via synaptic vesicle protein 2 A (SV2A) imaging remain unexplored. This study used ¹⁸F-SynVesT-1 PET to evaluate SV2A changes in tinnitus patients and compared them to ¹⁸F-FDG patterns. 28 tinnitus patients (acute/chronic) and 24 healthy controls underwent MRI and static PET with both ¹⁸F-SynVesT-1 and ¹⁸F-FDG. Standardized uptake values (SUV/SUVr) were calculated, followed by brain network analysis and EEG microstate assessment. Correlations with clinical features were examined. Lesions in the brain of chronic tinnitus patients had increased ¹⁸F-SynVesT-1 uptake compared with controls, corresponding to high metabolism detected by ¹⁸F-FDG PET. The patients revealed increased SV2A uptake of 14 brain areas, whereas the left inferior frontal gyrus showed decreased SV2A uptake. However, acute tinnitus patient results revealed a decreased synaptic density in five brain areas as compared to that of HCs. ¹⁸F-SynVesT-1 uptake had a more broaden pattern of induction than ¹⁸F-FDG in tinnitus lesions (P < 0.05). SUVR of these two imaging agents were positively correlated in insula lobe. Tinnitus Handicap Inventory (THI) scores negatively correlated with synaptic density in limbic regions. Brain network anaylsis showed that network connectivity was enhanced in tinnitus, highest acutely. Microstate analysis of EEG showed conserved microstate alternation. This first direct evidence demonstrates chronic tinnitus involves synaptic density elevation, while acute phase shows reduction, indicating bidirectional synaptic remodeling. ¹⁸F-SynVesT-1 outperforms ¹⁸F-FDG in detecting tinnitus-linked synaptic reorganization, with abnormality extent correlating to symptom severity, suggesting novel therapeutic targets for synaptic modulation.