Excitation-Inhibition Balance and Fronto-Limbic Connectivity Drive TMS Treatment Outcomes in Refractory Depression

Momi, D.; Wang, Z.; Oveisi, M. P.; Kadak, K.; Bastiaens, S. P.; Lissemore, J. I.; Noda, Y.; Downar, J.; Vila Rodriguez, F.; Strafella, R.; Daskalakis, Z. J.; Zrenner, C.; Zomorrodi, R.; Rolle, C. E.; Saggar, M.; Williams, N.; Keller, C. J.; Blumberger, D. M.; Voineskos, D.; Griffiths, J. D.

doi:10.1101/2025.04.23.648963

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bioRxiv · 10.1101/2025.04.23.648963

Excitation-Inhibition Balance and Fronto-Limbic Connectivity Drive TMS Treatment Outcomes in Refractory Depression

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Abstract

Depression affects over 350 million people worldwide, with treatment resistance occurring in up to 30% of cases. Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (DLPFC) has emerged as a promising intervention, yet the neurophysiological mechanisms determining which patients will respond remain poorly understood. Here, we combined transcranial magnetic stimulation with electroencephalography and whole-brain computational modeling to uncover the mechanistic basis of treatment efficacy in 90 patients with treatment-resistant depression. We identified two distinct neurophysiological signatures that differentiate responders from non-responders: (1) post-treatment shifts in excitation-inhibition balance toward greater inhibitory control, and (2) a pre-treatment brain state characterized by anticorrelated dynamics between subgenual anterior cingulate cortex and DLPFC. These features were significantly correlated with clinical improvement and could not be explained by non-specific factors. Our findings provide a neurophysiologically-informed framework for developing personalized and optimized neuromodulation approaches in treatment-resistant depression.

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Momi, D., Wang, Z., Oveisi, M. P., Kadak, K., Bastiaens, S. P., Lissemore, J. I., Noda, Y., Downar, J., Vila Rodriguez, F., Strafella, R., Daskalakis, Z. J., Zrenner, C., Zomorrodi, R., Rolle, C. E., Saggar, M., Williams, N., Keller, C. J., Blumberger, D. M., Voineskos, D., Griffiths, J. D.. 2025-04-29. Excitation-Inhibition Balance and Fronto-Limbic Connectivity Drive TMS Treatment Outcomes in Refractory Depression. https://doi.org/10.1101/2025.04.23.648963

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