Molecular Architecture of Temporal Variability Network Dysfunction in Bipolar Disorder

Characterized by recurrent fluctuations in mood states, bipolar disorder (BD) is widely conceptualized as a disconnection syndrome associated with dysregulated brain dynamics. Nevertheless, the molecular mechanisms underlying this aberrant connectivity dynamics in BD remain elusive. Using resting-state electroencephalography (EEG) data from BD patients and healthy controls, this study first delineated the characteristic alterations in temporal variability of functional connectivity in BD and further elucidated their underlying molecular mechanisms and clinical relevance. Current findings revealed significantly reduced temporal variability within large-scale brain subnetworks, most notably in the dorsal attention, somatomotor, and visual networks. Importantly, these neurodynamic signatures effectively predicted the symptom severity in individuals with BD. Moreover, the spatial patterns of these dynamic alterations are associated with the expression of BD risk genes enriched in synaptic function and metabolic pathways, as well as with the spatial organizations of various neurotransmitter receptors, including CB1, mGluR5, H3, and MOR. Collectively, these results provide evidence for a multiscale pathophysiological framework that links genetic susceptibility and chemoarchitectural alterations to dynamic brain network instability, ultimately underpinning the core clinical manifestations in BD.