Molecular mechanisms of electroconvulsive therapy modulates excitation-inhibition balance in major depression disorder.

BACKGROUND

The excitation-inhibition (E/I) imbalance is a major pathological characteristic of major depressive disorder (MDD). However, whether/how electroconvulsive therapy (ECT) modulates neuronal homeostasis or E/I balance in MDD and its molecular basis is still largely unknown.

METHODS

In this study, longitudinal rs-fMRI data from 46 patients with MDD receiving ECT and 46 healthy controls were included. The Hurst index was used to characterize the E/I balance, and mixed-effects model was constructed to assess the interactive effects of ECT on the Hurst index and functional connectivity (FC). Moreover, spatial correlation analyses were conducted by integrating cortical myelination pattern, glucose metabolism distribution, neurotransmitter density maps, and transcriptomic data to reveal the underlying molecular basis.

RESULTS

ECT significantly reduces the Hurst index in the middle cingulate cortex (MCC) and induces functional decoupling between the MCC and the posterior cingulate cortex. Furthermore, changes in the Hurst index were closely associated with cortical myelination, glucose metabolism, and the distribution maps of dopamine and histamine. Spatial transcriptomic association analysis revealed that genes regulating the effects of ECT on Hurst index or FC are specifically enriched in cell types such as excitatory neurons, astrocytes, and oligodendrocytes, and are primarily involved in biological processes including synaptic signal transduction, neuronal projection regulation, and glutamatergic synapses.

CONCLUSION

These findings suggest that ECT may regulate the processes of myelin remodelling through neurons and glial cells by influencing the expression levels of relevant genes, thereby modulating the E/I balance and functional network activity in a synergistic manner to improve depressive symptoms.