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; Patrick L Purdon

doi:10.1038/s41467-023-37463-3

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

Nat Commun. 2023 Mar 29;14(1):1748. doi: 10.1038/s41467-023-37463-3.

Authors

Fangyun Tian¹, Laura D Lewis^{2

3

4}, David W Zhou^{1

5

6}, Gustavo A Balanza¹, Angelique C Paulk^{7

8}, Rina Zelmann^{7

8}, Noam Peled³, Daniel Soper⁷, Laura A Santa Cruz Mercado¹, Robert A Peterfreund¹, Linda S Aglio⁹, Emad N Eskandar¹⁰, G Rees Cosgrove¹¹, Ziv M Williams¹², R Mark Richardson¹², Emery N Brown^{1

6}, Oluwaseun Akeju¹, Sydney S Cash^{7

8}, Patrick L Purdon¹³

Affiliations

¹ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Biomedical Engineering, Boston University, Boston, MA, USA.
³ Department of Radiology, MGH/HST Martinos Center for Biomedical Imaging and Harvard Medical School, Boston, MA, USA.
⁴ Institute for Medical Engineering and Sciences, Department of Electrical Engineering and Computer Science, Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Department of Neurological Surgery, Albert Einstein College of Medicine, Bronx, NY, USA.
¹¹ Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.
¹² Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹³ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. patrick.purdon@mgh.harvard.edu.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Antidepressive Agents / pharmacology
Antidepressive Agents / therapeutic use
Cerebral Cortex / metabolism
Humans
Ketamine* / pharmacology
Ketamine* / therapeutic use
N-Methylaspartate
Neurophysiology
Propofol* / pharmacology
Receptors, N-Methyl-D-Aspartate / metabolism

Substances

Ketamine
Propofol
N-Methylaspartate
Antidepressive Agents
Receptors, N-Methyl-D-Aspartate

Abstract

Publication types

MeSH terms

Substances

Grants and funding