Default Mode Network Reconfiguration Underlies Clinical Response to Amygdala-Targeted Neuromodulation in Major Depression

Major depressive disorder (MDD) is characterized by aberrant large-scale brain network dynamics, notably within the default mode network (DMN), which underpins maladaptive self-referential processing. We examined the clinical and neurophysiological effects of concurrent functional MRI-transcranial temporal interference stimulation (tTIS) targeting the right amygdala in 31 individuals with MDD. After five consecutive daily sessions, 61% of participants met clinical response criteria and 55% achieved remission, with symptom improvements largely maintained at four-week follow-up. Resting-state functional MRI revealed significant reductions in within-DMN functional connectivity immediately post-treatment alongside enhanced integration between the DMN and sensory-attentional networks. These network alterations correlated with clinical outcomes and persisted selectively in responders at follow-up. Dynamic analyses of high-amplitude co-fluctuation events identified distinct neural activation patterns linked to therapeutic benefit. Our results demonstrate sustained DMN reconfiguration as a core mechanism underlying the antidepressant effects of deep-targeted neuromodulation via tTIS, and highlight neuroimaging biomarkers predictive of treatment response. This study advances the understanding of network-level neuromodulatory mechanisms and supports the development of precision neurostimulation strategies for MDD.