Causal mechanisms of quadruple networks in pediatric bipolar disorder

Pediatric bipolar disorder (PBD) is characterized by abnormal functional connectivity among distributed brain regions. Increasing evidence suggests a role for the limbic network (LN) and the triple network model in the pathophysiology of bipolar disorder (BD). However, the specific relationship between the LN and the triple network in PBD remains unclear. This study aimed to investigate the aberrant causal connections among these four core networks in PBD.

Resting-state functional MRI scans from 92 PBD patients and 40 healthy controls (HCs) were analyzed. Dynamic Causal Modeling (DCM) was employed to assess effective connectivity (EC) among the four core networks. Parametric empirical Bayes (PEB) analysis was conducted to identify ECs associated with group differences, as well as depression and mania severity. Leave-one-out cross-validation (LOOCV) was used to test predictive accuracy.

Compared to HCs, PBD patients exhibited primarily excitatory bottom-up connections from the LN to the salience network (SN) and bidirectional excitatory connections between the default mode network (DMN) and SN. In PBD, top-down connectivity from the triple network to the LN was excitatory in individuals with higher depression severity but inhibitory in those with higher mania severity. LOOCV identified dysconnectivity circuits involving the caudate and hippocampus as being associated with mania and depression severity, respectively.

Disrupted bottom-up connections from the LN to the triple network distinguish PBD patients from healthy controls, while top-down disruptions from the triple network to LN relate to mood state differences. These findings offer insight into the neural mechanisms of PBD.