Cerebro-cerebellar functional neuroplasticity mediates the effect of electric field on electroconvulsive therapy outcomes.

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression and works by applying an electric current through the brain. The applied current generates an electric field (E-field) and seizure activity, changing the brain's functional organization. The E-field, which is determined by electrode placement (right unilateral or bitemporal) and pulse amplitude (600, 700, or 800 milliamperes), is associated with the ECT response. However, the neural mechanisms underlying the relationship between E-field, functional brain changes, and clinical outcomes of ECT are not well understood. Here, we investigated the relationships between whole-brain E-field (E brain , the 90 th percentile of E-field magnitude in the brain), cerebro-cerebellar functional network connectivity (FNC), and clinical outcomes (cognitive performance and depression severity). A fully automated independent component analysis framework determined the FNC between the cerebro-cerebellar networks. We found a linear relationship between E brain and cognitive outcomes. The mediation analysis showed that the cerebellum to middle occipital gyrus (MOG)/posterior cingulate cortex (PCC) FNC mediated the effects of E brain on cognitive performance. In addition, there is a mediation effect through the cerebellum to parietal lobule FNC between E brain and antidepressant outcomes. The pair-wise t-tests further demonstrated that a larger E brain was associated with increased FNC between cerebellum and MOG and decreased FNC between cerebellum and PCC, which were linked with decreased cognitive performance. This study implies that an optimal E-field balancing the antidepressant and cognitive outcomes should be considered in relation to cerebro-cerebellar functional neuroplasticity.