Abnormal functional lateralization and functional connectivity in thyroid-associated ophthalmopathy: mechanistic links to transcriptomic signatures and neurotransmitter systems.

Background: Thyroid-associated ophthalmopathy (TAO), characterized by eyelid retraction, proptosis, extraocular muscle hypertrophy, and pathological elevation of intraorbital pressure, represents a potentially devastating autoimmune disorder affecting both ocular structure and visual function. Emerging evidence demonstrates significant neurophysiological correlations in TAO pathogenesis, manifesting cerebral hemispheric specialization and cooperation; however, conventional methodologies failed to account for inherent anatomical asymmetries between cerebral hemispheres. Therefore, the present study used a new data analysis method to systematically interrogate hemispheric specialization and cooperation in TAO, while concurrently exploring its multi-omics correlations with transcriptomic signatures and neuromodulatory receptors/transporters.

Methods: A total of 32 patients with TAO and demographically matched healthy controls underwent high-resolution resting-state functional MRI. Whole-brain connectome matrices profiling autonomy index-functional homotope (CFH) interactions were generated to quantitatively characterize lateralized functional decoupling and transhemispheric coordination deficits in TAO. Voxel-wise aberrations in autonomy index/CFH metrics underwent multimodal correlation mapping with whole-transcriptome expression profiles and neurotransmitter receptor/transporter density atlases.

Results: Patients with TAO had higher abnormal autonomy index expression in the left inferior temporal gyrus; CFH values were reduced in the left cuneus, right cuneus, left precuneus, right precuneus, and left superior parietal. Enrichment analysis of genes associated with abnormal autonomy index and CFH values, respectively, revealed that these genes were mainly involved in synaptic development and regulation. Finally, in the density correlation analysis of abnormal CFH values with neurotransmitter receptors/transporters, significant correlations were found for 5-hydroxytryptamine (5-HT) 1A R, 5-HT 2A R, CB 1 R, GABA A R, M 1 R, and mGlu 5 R.

Conclusion: This multimodal investigation yields novel neurobiological insights into hemispheric dysregulation patterns in TAO, while elucidating the pathophysiological continuum of this complex disorder.