Intracranial directed connectivity links subregions of the prefrontal cortex to major depression

John Myers (), Jiayang Xiao, Raissa K. Mathura, Ben Shofty, Victoria Gates, Joshua Adkinson, Anusha B. Allawala, Adrish Anand, Ron Gadot, Ricardo Najera, Hernan G. Rey, Sanjay J. Mathew, Kelly Bijanki, Garrett Banks, Andrew Watrous, Eleonora Bartoli, Sarah R. Heilbronner, Nicole Provenza, Wayne K. Goodman, Nader Pouratian, Benjamin Y. Hayden and Sameer A. Sheth
Additional contact information
John Myers: Baylor College of Medicine
Jiayang Xiao: Baylor College of Medicine
Raissa K. Mathura: Baylor College of Medicine
Ben Shofty: Baylor College of Medicine
Victoria Gates: Baylor College of Medicine
Joshua Adkinson: Baylor College of Medicine
Anusha B. Allawala: Brown University
Adrish Anand: Baylor College of Medicine
Ron Gadot: Baylor College of Medicine
Ricardo Najera: Baylor College of Medicine
Hernan G. Rey: Baylor College of Medicine
Sanjay J. Mathew: Baylor College of Medicine
Kelly Bijanki: Baylor College of Medicine
Garrett Banks: Baylor College of Medicine
Andrew Watrous: Baylor College of Medicine
Eleonora Bartoli: Baylor College of Medicine
Sarah R. Heilbronner: Baylor College of Medicine
Nicole Provenza: Baylor College of Medicine
Wayne K. Goodman: University of Texas: Southwestern
Nader Pouratian: University of Texas: Southwestern
Benjamin Y. Hayden: Baylor College of Medicine
Sameer A. Sheth: Baylor College of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Research on the neural basis of major depressive disorder suggests that it is fundamentally a disease of cortical disinhibition, where breakdowns of inhibitory neuronal systems lead to diminished emotion regulation and intrusive rumination. Subregions of the prefrontal cortex are thought to be sources of this disinhibition. However, due to limited opportunities for intracranial recordings from humans with major depression, this hypothesis has not been directly tested. Here, we use intracranial recordings from the dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortices from patients with major depression to measure daily fluctuations in self-reported depression symptom severity. Results indicate that directed connectivity within the delta frequency band, which has been linked to cortical inhibition, transiently increases intensity during negative mood. Symptom severity also shifts as connectivity patterns within the left and right prefrontal cortices become imbalanced. Our findings support the overarching hypothesis that depression worsens with prefrontal disinhibition and functional imbalance between hemispheres.

Date: 2025
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DOI: 10.1038/s41467-025-61487-6

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