Frontiers in Neural Circuits
June 20, 2017
George A. Mashour, Anthony G. Hudetz
136 citations
General anesthetics may suppress consciousness through two complementary neural pathways: a bottom-up mechanism that alters arousal by acting on brainstem and diencephalon sleep-wake nuclei, and a top-down mechanism that disrupts cortical and thalamocortical circuits responsible for integrating information. This article synthesizes these approaches by mapping them to two interrelated dimensions of consciousness—level and content. The framework explains why different anesthetic drugs produce diverse effects on subjective experience. The authors argue that level and content interact to generate consciousness, and understanding this interaction is key to explaining how anesthetics induce unconsciousness.
Anesthesia & Analgesia
June 23, 2016
Anthony G. Hudetz, George A. Mashour
128 citations
A systems-level neuroscientific basis for anesthetic-induced loss and return of consciousness has been sought for two decades. Advances using electrophysiology, EEG, MEG, and fMRI show that specific and common changes in functional and effective connectivity across large-scale brain networks occur during anesthesia. Most investigations converge on the conclusion that a consistent depression or functional disconnection of lateral frontoparietal networks correlates with anesthetic-induced unresponsiveness, as these networks are thought critical for environmental consciousness. A reduction in brain state repertoire may disrupt large-scale information integration, leading to unconsciousness. Future work should systematically delineate connectivity changes across anesthetics and identify behavior-independent measures of subjective experience.
Cell Reports
May 1, 2021
Zirui Huang, Vijay Tarnal, Phillip E. Vlisides et al.
119 citations
Conscious access to sensory information is likely gated at an intermediate site between primary sensory and transmodal association cortices, with the anterior insular cortex (AIC) playing a key role. Functional neuroimaging using a volitional mental imagery task in healthy volunteers, with propofol titrated to loss of behavioral responsiveness, showed that AIC dysfunction is associated with impaired transitions between default-mode and dorsal attention networks. Candidate subcortical regions such as the thalamus and basal forebrain did not show this association. In awake participants, pre-stimulus AIC activity near perceptual threshold predicted conscious access. These findings support the hypothesis that AIC regulates brain network transitions that gate conscious access.
Cerebral Cortex
July 10, 2013
Gustavo Deco, P. Hagmann, Anthony G. Hudetz et al.
99 citations
The transition from wakefulness to sleep involves gradual neural changes rather than an abrupt shift. Local slow waves appear during wakefulness and increase as arousal-promoting neuromodulation decreases, while resting-state brain networks maintain their overall organization. Only when neuromodulation drops to very low levels do slow waves become global and resting-state networks merge into a single synchronized network.
Nature Communications
September 9, 2024
Zirui Huang, George A. Mashour, Anthony G. Hudetz
23 citations
Anesthesia-induced unconsciousness involves a shift in the functional geometry of thalamocortical circuits, moving from a normal unimodal-transmodal pattern to a transmodal-deficient one. This alteration is linked to spatial variations in matrix cell composition within the thalamus, suggesting that disrupted connectivity of matrix cells plays a key role in the loss of consciousness. The study used functional magnetic resonance imaging in healthy volunteers during conscious baseline, deep sedation, and recovery, applying a functional gradient mapping technique to delineate these changes. The findings bridge cellular and systems-level understanding of consciousness.
Commun Biol
December 19, 2023
Rui Dai, Zirui Huang, Tony E. Larkin et al.
7 citations
At concentrations that produce psychedelic effects, nitrous oxide reduces the functional differentiation—the distinctness of activity patterns—within frontoparietal and somatomotor cortical networks. This suggests that the gas alters brain network organization, potentially contributing to its consciousness-altering properties. The finding points to a neural mechanism underlying the non-ordinary state induced by nitrous oxide, involving reduced specialization of key brain regions.
bioRxiv (Cold Spring Harbor Laboratory)
October 14, 2025
Nicholas Kolbman, Amanda Nelson, Rachel Summerfield et al.
1 citation
preprint
Psilocybin and DMT, two serotonergic psychedelics, delay the onset of slow-wave sleep and REM sleep, and cause a short-lasting increase in wakefulness and decrease in slow-wave sleep in rats. Psilocybin also reduces REM sleep, decreases theta power and coherence, and increases high gamma power and coherence during wake and slow-wave sleep, as well as increasing high gamma coherence during REM sleep. DMT increases gamma coherence only during wakefulness. The enhanced high gamma functional connectivity suggests that psychedelic-induced changes in neural dynamics can occur independently of arousal states.
bioRxiv
November 26, 2025
Rui Dai, Rodrigo Cofré, Christopher Timmermann et al.
preprint
Classical psychedelics (DMT, LSD, psilocybin) and non-classical ones (nitrous oxide, ketamine) all disrupt local synchrony in small brain regions (<1 cm³) in humans, as measured by functional magnetic resonance imaging. This disruption occurred extensively in cortical regions and sparsely in subcortical regions. As local synchrony declined, large-scale functional connectivity increased. For classical psychedelics, the disruption was most strongly associated with 5-HT receptors; for nitrous oxide and ketamine, it was most strongly associated with NMDA receptors. Both neuronal and non-neuronal cell types were linked to these changes. The findings suggest diverse molecular events converge on a common outcome of disrupted local synchrony, which then mediates drug-specific global connectivity changes.