Repetitive Transcranial Magnetic Stimulation Reversing Abnormal Brain Function in Mood Disorders with Early Life Stress: from preclinical models to clinical applications

Background: Early life stress (ELS) significantly increases the risk of mood disorders and affects the neurodevelopment of the primary cortex. Hypothesis: Modulating the primary cortex through neural intervention can ameliorate the impact of ELS on brain development and consequently alleviate its effects on mood disorders. Method: We induced the chronic unpredictable mild stress (CUMS) model in adolescent rats, followed by applying repetitive transcranial magnetic stimulation (rTMS) to their primary cortex in early adulthood. To assess the applicability of primary cortex rTMS in humans, we recruited individuals aged 17 -25 with mood disorders who had experienced ELS and performed primary cortex rTMS on them. Functional magnetic resonance imaging (fMRI) and depression -related behavioral and clinical symptoms were conducted in both rats and human subjects before and after the rTMS. Results: In animals, fMRI analysis revealed increased activation in the primary cortex of CUMS rats and decrease subcortical activation. Following the intervention of primary cortex rTMS, the abnormal functional activity was reversed. Similarly, in mood disorders patients with ELS, increased activation in the primary cortex and decreased activation in the frontal cortex were observed. During rTMS intervention, similar neuroimaging improvements were noted, particularly decreased activation in the primary cortex. This suggests that targeted rTMS in the primary cortex can reverse the abnormal neuroimaging. Conclusion: This cross -species translational study has identified the primary cortex as a key region in mood disorders patients with ELS. Targeting the primary cortex with rTMS can correct abnormal functional activity while improving symptoms. Our study provides translational evidence for therapeutics targeting the ELS factor of mood disorders patients.