Science Translational Medicine
May 1, 2024
Brian L Edlow, Mark Olchanyi, Holly J Freeman et al.
39 citations
A proposed subcortical arousal network, crucial for wakefulness, has been mapped in the human brain, revealing connections between key areas like the brainstem and hypothalamus. Utilizing data from three neurologically normal individuals' brains and advanced imaging techniques, this study identified pathways linking the default ascending arousal network with the cortical default mode network. Notably, the dopaminergic ventral tegmental area emerged as a central hub connecting these networks. This work enhances our understanding of how arousal and awareness integrate in human consciousness.
Proceedings of the National Academy of Sciences of the United States of America
October 15, 2024
Yihan Sophy Xiong, Jacob Donoghue, Mikael Lundqvist et al.
32 citations
Predictive coding in the cortex relies on predictions fed back from deep layers via alpha/beta oscillations (8–30 Hz) that inhibit gamma (40–100 Hz) and spiking carrying sensory input forward. Intracranial recordings in macaques during passive auditory oddball tasks showed that in the awake state alpha/beta oscillations inhibited processing of predictable sounds. Propofol-induced loss of consciousness eliminated this alpha/beta modulation in sensory cortex and reduced alpha/beta coherence between sensory and frontal areas. Consequently, oddball stimuli evoked enhanced gamma power, late spiking, and superficial layer sinks in auditory cortex, indicating a disinhibited state. However, differential spiking to oddballs in higher-order cortex was lost, likely due to disrupted spike-field coupling. These findings constrain theories of consciousness.
PLoS Computational Biology
August 18, 2021
Indie C. Garwood, S. Chakravarty, Jacob Donoghue et al.
32 citations
Ketamine, an anesthetic that blocks NMDA receptors, produces alternating bursts of gamma (25-50 Hz) and slow-delta (0.1-4 Hz) brain oscillations. A hidden Markov model fitted to local field potentials from two non-human primates and electroencephalograms from nine humans quantified these dynamics. Gamma activity lasted on average 2.2 seconds in one primate, 1.2 in the other, and 2.5 in humans; slow-delta lasted 1.6, 1.0, and 1.8 seconds respectively. Five sub-states with regular sequential transitions were identified. These findings provide quantitative constraints for models of rhythm generation underlying ketamine-induced altered arousal.
Proceedings of the National Academy of Sciences of the United States of America
May 28, 2024
Elie Adam, Marek Kowalski, Oluwaseun Akeju et al.
30 citations
Ketamine, an NMDA-receptor antagonist, produces sedation and dissociation at low doses and unconsciousness at high doses, while generating gamma oscillations (>25 Hz) in the EEG that are interrupted by slow-delta oscillations (0.1–4 Hz) at high doses. Using a biophysical model of cortical circuits, the authors show how NMDA-receptor antagonism leads to disinhibition in neuronal circuits, and how disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition produces gamma oscillations at both doses and slow-delta oscillations at high doses. This work reveals general mechanisms for generating oscillatory brain dynamics and provides insights into ketamine's actions as an anesthetic and therapy for treatment-resistant depression.
Annual Review of Neuroscience
February 19, 2025
Macauley Smith Breault, Sirma Orguc, Ohyoon Kwon et al.
13 citations
Several anesthetic agents beyond ketamine show antidepressant effects, including nitrous oxide, propofol, isoflurane, sevoflurane, dexmedetomidine, and xenon. This review examines clinical and basic science studies on these anesthetics for treating depression. The authors propose that anesthetics may alleviate depression by modulating brain dynamics that alter arousal states, linking anesthetic mechanisms to depression pathophysiology and findings from other treatments. The work suggests that repurposing anesthetics could offer new options for major depressive disorder and treatment-resistant depression.
Cell Reports
May 27, 2025
Alexandra G Bardon, Jesus J Ballesteros, Scott L Brincat et al.
8 citations
Two anesthetics with different molecular actions, ketamine and dexmedetomidine, both increase phase locking of neural oscillations in the prefrontal cortex of nonhuman primates during loss of responsiveness. Within a hemisphere, neighboring prefrontal subregions become less phase-aligned, possibly due to large traveling waves. However, homologous areas across hemispheres become more aligned in phase. These distinct patterns of cortical phase alignment, markedly different from waking states, may represent a common mechanism by which diverse anesthetics produce loss of responsiveness.
bioRxiv Preprint Server
April 3, 2024
Elie Adam, Marek Kowalski, Oluwaseun Akeju et al.
5 citations
preprint
Ketamine, an NMDA-receptor antagonist, produces sedation, analgesia, and dissociation at low doses and unconsciousness at high doses, generating gamma oscillations (>25 Hz) in the EEG at both doses, with slow-delta oscillations (0.1-4 Hz) interrupting gamma at high doses. Using a biophysical model of cortical circuits, the authors show how NMDA-receptor antagonism by ketamine leads to disinhibition in neuronal circuits, and how the disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition generates gamma oscillations at both doses and slow-delta oscillations at high doses. This work reveals general mechanisms for oscillatory brain dynamics distinct from previous reports and offers insights into ketamine's action as an anesthetic and therapy for treatment-resistant depression.
Nature and Science of Sleep
January 1, 2025
David R Schreier, Matteo Fecchio, Christian S Guay et al.
Dexmedetomidine (DEX) is a sedative that produces a sleep-like state and offers a way to study shifts in consciousness using behavior, EEG, and TMS-evoked EEG responses. Little is known about how repeated DEX exposure affects recovery. This pilot trial plans to sedate 12 healthy volunteers twice, one week apart, monitoring responsiveness with an auditory click task. It will compare time to return of responsiveness between visits, explore sex differences, and assess state transitions via EEG signatures, TMS-evoked complexity, and cognitive tests. The study also evaluates the feasibility of TMS-EEG during DEX sedation and reports on sleep quality and experiences.
bioRxiv Preprint Server
May 2, 2022
Fangyun Tian, Laura D. Lewis, David W. Zhou et al.
preprint
A subanesthetic dose of ketamine increases gamma oscillations in the prefrontal cortex and hippocampus, brain areas linked to its rapid antidepressant effects, and produces a 3 Hz oscillation in the posteromedial cortex that may underlie its dissociative effects. By adding propofol, which blocks NMDA-mediated disinhibition and shares HCN1 inhibition with ketamine, the study distinguished brain dynamics caused by NMDA-mediated disinhibition from those caused by HCN1 inhibition. The results suggest ketamine engages distinct neural circuits in frequency-dependent patterns to produce antidepressant and dissociative effects, potentially guiding development of new depression therapies with fewer side effects.
medRxiv Preprint Server
November 12, 2020
Indie C. Garwood, Sourish Chakravarty, Jacob Donoghue et al.
preprint
Ketamine, an anesthetic and psychoactive drug, produces alternating patterns of brain activity: bursts of gamma oscillations (30-50 Hz) and slow oscillations (0.1-10 Hz). A hidden Markov model (HMM) was applied to brainwave data from two non-human primates and nine human subjects receiving anesthetic doses of ketamine. The model revealed distinct states corresponding to gamma bursts and slow oscillations, with intermediate states. Mean gamma burst durations were 2.5 seconds (non-human primate 1), 1.2 seconds (non-human primate 2), and 2.7 seconds (humans). Mean slow oscillation durations were 1.6 seconds, 0.7 seconds, and 2.8 seconds, respectively. This framework provides quantitative constraints for understanding how ketamine alters states of consciousness.
bioRxiv Preprint Server
July 13, 2023
Brian L Edlow, Mark Olchanyi, Holly J Freeman et al.
preprint
Consciousness depends on both arousal (wakefulness) and awareness. While cortical networks for awareness are well studied, the subcortical networks supporting arousal are less understood. By combining ex vivo diffusion MRI, immunohistochemistry, and in vivo 7 Tesla functional MRI in three human brain specimens, the authors identified a default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain. They mapped connections within the dAAN and between the dAAN and the cortical default mode network (DMN), suggesting a structural basis for integrating arousal and awareness. The data and methods are released to aid further mapping of human consciousness.