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

Author

Listed:
  • Fangyun Tian

    (Massachusetts General Hospital, Harvard Medical School)

  • Laura D. Lewis

    (Boston University
    MGH/HST Martinos Center for Biomedical Imaging and Harvard Medical School
    Massachusetts Institute of Technology)

  • David W. Zhou

    (Massachusetts General Hospital, Harvard Medical School
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Gustavo A. Balanza

    (Massachusetts General Hospital, Harvard Medical School)

  • Angelique C. Paulk

    (Harvard Medical School
    Massachusetts General Hospital)

  • Rina Zelmann

    (Harvard Medical School
    Massachusetts General Hospital)

  • 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
    Massachusetts Institute of Technology)

  • Oluwaseun Akeju

    (Massachusetts General Hospital, Harvard Medical School)

  • Sydney S. Cash

    (Harvard Medical School
    Massachusetts General Hospital)

  • Patrick L. Purdon

    (Massachusetts General Hospital, Harvard Medical School)

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.

Suggested Citation

  • 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. Agli, 2023. "Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37463-3
    DOI: 10.1038/s41467-023-37463-3
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    as
    1. Sam Vesuna & Isaac V. Kauvar & Ethan Richman & Felicity Gore & Tomiko Oskotsky & Clara Sava-Segal & Liqun Luo & Robert C. Malenka & Jaimie M. Henderson & Paul Nuyujukian & Josef Parvizi & Karl Deisser, 2020. "Deep posteromedial cortical rhythm in dissociation," Nature, Nature, vol. 586(7827), pages 87-94, October.
    2. Michael J Prerau & Katie E Hartnack & Gabriel Obregon-Henao & Aaron Sampson & Margaret Merlino & Karen Gannon & Matt T Bianchi & Jeffrey M Ellenbogen & Patrick L Purdon, 2014. "Tracking the Sleep Onset Process: An Empirical Model of Behavioral and Physiological Dynamics," PLOS Computational Biology, Public Library of Science, vol. 10(10), pages 1-19, October.
    3. Panos Zanos & Ruin Moaddel & Patrick J. Morris & Polymnia Georgiou & Jonathan Fischell & Greg I. Elmer & Manickavasagom Alkondon & Peixiong Yuan & Heather J. Pribut & Nagendra S. Singh & Katina S. S. , 2016. "NMDAR inhibition-independent antidepressant actions of ketamine metabolites," Nature, Nature, vol. 533(7604), pages 481-486, May.
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