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.

The neural basis of consciousness remains a major unresolved issue in human neuroscience, with theories of consciousness and experimental studies differing concerning which brain regions are necessary for consciousness. Direct experimental evidence to resolve this debate requires identifying the global, network, and regional involvement during different states of consciousness in humans. We utilized multi-region intracranial single-pulse direct electrical stimulation to examine circuit and network interactions during three canonical states of consciousness: wake vs. arousable unconsciousness (sleep) vs. non-arousable unconsciousness (e.g., propofol-induced general anesthesia). Increased variability in cortical responses, reduced information transfer, and reduced complexity characterized states of diminished consciousness. Notably, however, these metrics differed in different brain regions and types of unconscious states.Anesthesia induced more overall changes in brain responses than sleep, but cortical network engagement depended on the kind of unconsciousness. Brain activity changes were largely anatomically uniform during sleep, contrasting with a substantial and selective disconnection of the prefrontal cortices during anesthesia. These results provide direct evidence from human intracranial recordings during the loss of consciousness, suggesting that the obliteration of consciousness during anesthesia results not from just altered overall physiology but from a disconnection between prefrontal areas and other brain areas. Significance What happens in the human brain when we are unconscious? Despite substantial work, we are still unsure which brain regions are involved and how they are impacted when consciousness is disrupted. Using intracranial recordings and direct electrical stimulation, we mapped global, network, and regional involvement during wake vs. arousable unconsciousness (sleep) vs. non-arousable unconsciousness (propofol-induced general anesthesia). Information integration and complex processing were reduced, while variability increased during the loss of consciousness. These changes were more pronounced during anesthesia than sleep. They also involved different cortical engagement; During sleep, changes were mostly uniformly distributed across the brain while during anesthesia the prefrontal cortex was the most disrupted. These findings indicate different neural signatures for different types of unconsciousness. Highlights · Sleep and anesthesia showed decreased complexity, connectivity, and response amplitude with increased response variability compared to wake states in the human brain. · These changes in brain response to stimulation were more pronounced during propofol-induced general anesthesia than during natural sleep. · During sleep, changes were homogeneously distributed across the brain. · During anesthesia, there was a substantial disconnection of the frontal cortices.

What happens in the human brain when we are unconscious? Despite substantial work, we are still unsure which brain regions are involved and how they are impacted when consciousness is disrupted. Using intracranial recordings and direct electrical stimulation, we mapped global, network, and regional involvement during wake vs. arousable unconsciousness (sleep) vs. non-arousable unconsciousness (propofol-induced general anesthesia). Information integration and complex processing were reduced, while variability increased in any type of unconscious state. These changes were more pronounced during anesthesia than sleep. They also involved different cortical engagement; During sleep, changes were mostly uniformly distributed across the brain while during anesthesia the prefrontal cortex was the most disrupted, suggesting that the obliteration of consciousness during anesthesia results not from just altered overall physiology but from a disconnection between prefrontal and other brain areas. These findings provide direct evidence of the different neural signatures for different types of unconsciousness.

SummarySubanesthetic doses of ketamine produce rapid and sustained anti-depressant effects in patients with treatment-resistant depression. Unfortunately, the usefulness of ketamine as a treatment is limited by its potential for abuse because of psychotropic side effects such as dissociation. Understanding the brain dynamics and the neural circuits involved in ketamine’s effects could lend insight into improved therapies for depression with fewer adverse effects. It is believed that ketamine acts via NMDA receptor and hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels to produce changes in oscillatory brain dynamics. Here we show, in humans, a detailed description of the principal oscillatory changes in cortical and subcortical structures by administration of a subanesthetic dose of ketamine. Using recordings from intracranial electrodes, we found that ketamine increased gamma oscillations within prefrontal cortical areas and the hippocampus--structures previously implicated in ketamine’s antidepressant effects. Furthermore, our studies provide direct evidence of a ketamine-induced 3 Hz oscillation in posteromedial cortex that has been proposed as a mechanism for its dissociative effects. By analyzing changes in neural oscillations after the addition of propofol, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition alongside a shared HCN1 inhibitory effect, we identified brain dynamics that could be attributed to NMDA-mediated disinhibition versus HCN1 inhibition. Overall, our results imply 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 novel brain dynamic biomarkers and therapeutics for depression.

The neural basis of consciousness remains a major unresolved issue in human neuroscience. To better understand how cortical networks are engaged during different states of consciousness, we utilized multi-region intracranial single-pulse direct electrical stimulation to examine circuit and network interactions during three canonical states of consciousness: wake, sleep, and under propofol-induced general anesthesia. Increased variability in cortical responses, reduced information transfer, and reduced complexity characterized states of diminished consciousness. Notably, however, these metrics differed in different brain regions and types of unconscious states. Anesthesia induced more overall changes in brain responses than sleep. Brain activity changes were largely anatomically uniform during sleep, contrasting with a substantial and selective disconnection of the prefrontal cortices during anesthesia. These results suggest that the obliteration of consciousness during anesthesia results not from just altered overall physiology but from a disconnection between prefrontal areas and other brain areas.