Cerebello-frontal effective dysconnectivity and reduced white matter integrity promote manic symptoms in bipolar disorder

Aim Bipolar disorder (BD) is considered a disconnection syndrome, where symptoms are not attributed to focal brain alterations, but rather to changes in the anatomo-functional integration across brain networks. This suggests investigating patients’ brain structural connectivity and integrity as well as their functional and effective connectivity at rest. Particularly the latter, given its potential to reveal the origin of disconnections and their contribution to the observed symptoms. Methods In the present study, 148 type-I BD and 114 typically developing (TD) individuals underwent functional magnetic resonance imaging (fMRI) and diffusion-tensor imaging (DTI). Current mood symptomatology in BD patients was evaluated using Hamilton depression rating scale (HAM-D) and Young mania rating scale (YMRS). Results After comparing both basal activity and FC differences between groups and their relationship with patients’ symptomatology, FC between right Crus II and left superior frontal gyrus (SFG) was found inversely correlated with YMRS scores. Spectral direct causal modelling (spDCM) revealed that the physiological pattern of EC between the two regions, facilitatory from CrusII–to-SFG and inhibitory in the opposite direction, was absent in BD patients. While fronto-cerebral-ponto-cerebellar (FCPC) tract integrity did not differ between groups, cerebello-thalamo-cortical (CTC) one was reduced in BD and positively correlated with the facilitatory drive from Crus II to SFG. Conclusions These findings suggest that reduced CTC tract integrity may affect the physiological ability of Crus II to upregulate SFG activity, potentially contributing to the persistence of manic symptoms. These insights underscore the importance of targeting cerebello-cortical pathways in future therapeutic interventions for BD.