Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology

Fangyun Tian, Laura D. Lewis, David W. Zhou, Gustavo A. Balanza, Angelique C. Paulk, Rina Zelmann, Noam Peled, Daniel Soper, Laura A. Santa Cruz Mercado, Robert A. Peterfreund, Linda S. Aglio, Emad N. Eskandar, G. Rees Cosgrove, Ziv M. Williams, R. Mark Richardson, Emery N. Brown, Oluwaseun Akeju, Sydney S. Cash and Patrick L. Purdon ()
Additional contact information
Fangyun Tian: Massachusetts General Hospital, Harvard Medical School
Laura D. Lewis: Boston University
David W. Zhou: Massachusetts General Hospital, Harvard Medical School
Gustavo A. Balanza: Massachusetts General Hospital, Harvard Medical School
Angelique C. Paulk: Harvard Medical School
Rina Zelmann: Harvard Medical School
Noam Peled: MGH/HST Martinos Center for Biomedical Imaging and Harvard Medical School
Daniel Soper: Harvard Medical School
Laura A. Santa Cruz Mercado: Massachusetts General Hospital, Harvard Medical School
Robert A. Peterfreund: Massachusetts General Hospital, Harvard Medical School
Linda S. Aglio: Brigham and Women’s Hospital
Emad N. Eskandar: Albert Einstein College of Medicine
G. Rees Cosgrove: Brigham and Women’s Hospital
Ziv M. Williams: Harvard Medical School
R. Mark Richardson: Harvard Medical School
Emery N. Brown: Massachusetts General Hospital, Harvard Medical School
Oluwaseun Akeju: Massachusetts General Hospital, Harvard Medical School
Sydney S. Cash: Harvard Medical School
Patrick L. Purdon: Massachusetts General Hospital, Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine’s antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects. We analyzed oscillatory changes after subsequent propofol administration, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition, alongside a shared HCN1 inhibitory effect, to identify dynamics attributable to NMDA-mediated disinhibition versus HCN1 inhibition. Our results suggest that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of brain dynamic biomarkers and novel therapeutics for depression.

Date: 2023
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DOI: 10.1038/s41467-023-37463-3

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