Intrinsic neural timescale abnormalities reveal molecular and neuromodulatory basis of concomitant exotropia

Concomitant exotropia (CE) is a prevalent strabismic disorder characterized by outward ocular deviation and impaired binocular vision. While structural and functional brain abnormalities have been reported in CE, the temporal dynamics of intrinsic neural timescale remain largely unexplored.

This study employed a multimodal framework combining resting-state functional MRI (rs-fMRI), transcriptomic data from the Allen Human Brain Atlas (AHBA), and neurotransmitter receptor density maps to investigate alterations in intrinsic neural timescales (INT) in CE. A total of 87 participants (43 CE patients, 44 matched controls) underwent rs-fMRI scanning. Voxel-wise and network-level INT were computed, followed by partial least squares (PLS) regression linking INT alterations with regional gene expression. Functional enrichment, cell-type specificity, and spatial correlations with PET-based receptor maps were also analyzed.

Compared to controls, CE patients exhibited significantly reduced INT in the right middle frontal gyrus and basal ganglia network, indicating impaired temporal integration in oculomotor and executive control circuits. Transcriptomic analyses revealed that INT-related genes were enriched for immune-inflammatory and neurodevelopmental pathways. Excitatory and inhibitory neurons were the dominant contributors to the altered transcriptional profiles, implicating excitation-inhibition imbalance as a core mechanism. Furthermore, INT alterations showed significant negative correlations with glutamatergic, GABAergic, and opioid receptor distributions, suggesting neuromodulatory dysregulation in CE.

This study provides the first evidence of altered INT in CE and uncovers their molecular and neurochemical substrates. The findings highlight INT as a sensitive biomarker for temporal dysfunction in CE and emphasize the utility of integrative imaging-genomic approaches in elucidating its pathophysiology.