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.
Neuroimage
May 1, 2021
Pengmin Qin, Xuehai Wu, Changwei W Wu et al.
51 citations
Consciousness depends on a network of brain regions that integrate sensory and motor information. Analyzing fMRI data from people in preserved (awake, fully conscious brain-injury survivors), reduced (N1-sleep, minimally conscious), and lost (N3-sleep, anesthesia, unresponsive wakefulness) states, plus a unique rapid-eye-movement (REM) sleep group, researchers identified key hubs whose degree centrality—a measure of network importance—dropped significantly when consciousness was reduced or absent. These hubs included the supplementary motor area, bilateral supramarginal gyrus, supragenual/dorsal anterior cingulate cortex, and left middle temporal gyrus. A higher-order sensorimotor circuit connecting these regions showed functional connectivity that correlated with consciousness levels across groups and remained active in REM sleep, suggesting this circuit supports consciousness and offers new targets for treating disorders of consciousness.
Neuroimage
June 1, 2023
Rui Dai, Tony E. Larkin, Zirui Huang et al.
49 citations
Three different psychedelics—nitrous oxide, ketamine, and lysergic acid diethylamide—produce a common pattern of brain network changes despite having distinct molecular mechanisms and delivery methods. Each drug reduced connectivity within brain networks and enhanced connectivity between networks. Specifically, all three increased connections between the right temporoparietal junction and bilateral intraparietal sulcus, and between the precuneus and left intraparietal sulcus. These regions lie within the posterior cortical "hot zone," an area thought to mediate the qualitative aspects of experience. The findings identify a biologically plausible candidate for the subjective effects of both classical and non-classical psychedelics.
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 : the preprint server for biology
October 23, 2024
Rui Dai, Hyunwoo Jang, Anthony G. Hudetz et al.
1 citation
preprint
Consciousness appears to depend on global interactions across multiple brain regions rather than on localized neural activity. Using fMRI data across psychedelic, sleep, and deep sedation states, the study found a mirror-image pattern: psychedelic states increased global functional connectivity and decreased local neural synchrony, while non-REM sleep and deep sedation showed the opposite pattern. This pattern was observed in anterior-posterior and posterior-posterior brain regions but not within the anterior brain alone. Anterior transmodal regions were key for anterior-posterior connectivity, while posterior transmodal and unimodal regions were critical for posterior-posterior connectivity. The findings support global theories of consciousness and bridge the Global Neuronal Workspace hypothesis and Integrated Information Theory by showing shared neural mechanisms.
bioRxiv : the preprint server for biology
June 1, 2026
Panagiotis Fotiadis, Hyunwoo Jang, Rui Dai et al.
Brain waves coordinate neural communication and shape conscious perception. Analyzing blood oxygen level-dependent activity from the Human Connectome Project and other datasets across sleep, propofol anesthesia, and psychedelic states (LSD, DMT, psilocybin, nitrous oxide, ketamine), four dominant wave propagation motifs were identified: a global synchronized wave, an anti-correlated unimodal-transmodal wave, an anti-correlated task-positive/task-negative wave, and an anti-correlated visual-somatomotor wave.
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.
Cambridge quarterly of healthcare ethics : CQ : the international journal of healthcare ethics committees
January 3, 2025
Matthew Owen, Darren Hight, Anthony G. Hudetz
Some brain-injured patients who appear unresponsive can covertly answer simple questions through neuronal responses, raising the possibility of including them in low-stakes medical decisions to protect their autonomy. The warrant for crediting these neuronal responses is analyzed from neurology, bioethics, law, and philosophy of mind. Nonreductive physicalism's causal exclusion problem casts doubt on interpreting neural activity as indicating a conscious response, while a hylomorphism-inspired mind-body powers model supports such interpretation.
Nature Communications
October 24, 2024
Hyunwoo Jang, George A. Mashour, Anthony G. Hudetz et al.
A metric called the integration-segregation difference (ISD), derived from fMRI data, captures two key brain network properties: efficiency (integration) and clustering (segregation). During anesthesia with propofol, brain networks shift profoundly toward segregation as consciousness is lost. A common sequence of disintegration and reintegration occurs in unimodal and transmodal networks during loss and return of responsiveness. Machine learning models using these measures accurately identify awake versus unresponsive states. Metastability is more closely linked to integration, while complexity is linked to segregation. Similar patterns appear in sleep. The ISD reliably indexes states of consciousness.
Brain Sciences
August 30, 2024
Hyunwoo Jang, Rui Dai, George A. Mashour et al.
A machine learning model that combines functional connectivity, graph-theoretic metrics, and cortical gradient features can classify brain states—including unconsciousness (NREM2 sleep, propofol sedation and anesthesia), psychedelic states (ketamine, LSD, nitrous oxide), and neuropsychiatric disorders (ADHD, bipolar disorder, schizophrenia)—with an average balanced accuracy of 79% (range 62–98%). The ensemble model outperformed individual feature-based models (70–76%). Transferability across datasets varied, and feature importance analysis indicated that different brain states rely on distinct neural mechanisms, suggesting that tailored approaches are needed for accurate classification. The findings highlight the value of integrating multiple feature types for robust brain-state classification, though further work is needed for broader generalizability.
Frontiers in Neuroscience
January 1, 2024
Anthony G. Hudetz
Intracortical microstimulation in rat visual cortex reveals that anesthesia dramatically reduces the density and complexity of effective connectivity among neurons compared to wakefulness. Stimulation caused an early increase in spiking followed by a prolonged decrease. Excitatory neurons' early responses decayed rapidly with distance under all conditions. Network motifs, especially higher-order ones, increased substantially as anesthesia was withdrawn, indicating a large increase in network connectivity as animals woke up. The findings illuminate how anesthesia impacts the functional integrity of local cortical circuits, affecting the state of consciousness.
Cambridge quarterly of healthcare ethics : CQ : the international journal of healthcare ethics committees
October 18, 2023
Matthew Owen, Zirui Huang, Catherine Duclos et al.
Human cerebral organoids (HCOs), grown from stem cells to mimic developing brain tissue, may eventually manifest rudimentary consciousness, despite current limitations. Since HCOs provide no behavioral indicators of consciousness, this article applies three neurobiological theories—the Temporal Circuit Hypothesis, the Global Neuronal Workspace Theory, and the Integrated Information Theory—to assess whether HCOs could possess a neurobiological capacity for consciousness, analogous to how these theories are used with unresponsive brain-injured patients.
Entropy
July 10, 2018
Heonsoo Lee, Zirui Huang, Xiaolin Liu et al.
Permutation entropy (PE) and symbolic mutual information (SMI) analysis of fMRI data from 15 healthy participants under propofol sedation reveals that anesthesia differentially affects local and shared brain information. Global PE decreased from wakefulness to deep (unconscious) sedation and increased upon recovery, with greater reduction in subcortical than cortical networks. SMI's spatial pattern (topographic structure) reconfigures during unconsciousness, and the positive correlation between PE and SMI seen in conscious states is disrupted in deep sedation. PE changes preferentially occur in highly connected hub regions. These results suggest that altered local and shared information exchange is a mechanistic indicator of anesthetic-induced unconsciousness.
Frontiers in Psychology
September 16, 2014
Talis eBachmann, Anthony G. Hudetz
Consciousness arises from the interaction of two distinct brain mechanisms: one that represents the specific contents of perception and cognition (the data) and another that regulates the level of activity of those contents. Neither mechanism alone is sufficient; without specific contents there is no conscious experience, and without sufficient activity those contents remain unconscious. When both are activated to the necessary degree, they jointly provide conditions sufficient for conscious experience to emerge. This theoretical integration combines two previously separate research traditions—one studying the contents of conscious experience and the other studying the level of consciousness—and emphasizes understanding the mechanisms of consciousness rather than mere correlates.
Rui Dai, Hyunwoo Jang, Anthony G. Hudetz et al.
Across altered states of consciousness, psychedelics and sedatives produce opposite patterns of brain network organization. Psychedelics increase large-scale integration and reduce segregation of brain network interactions, while sleep and propofol sedation show the opposite pattern. These opposing integration-segregation patterns were consistently observed across multiple measures of functional connectivity, network topology, and interaction complexity, and reliably differentiated conscious states in an unbiased, data-driven manner. The findings demonstrate that psychedelic and sedated states are characterized by systematic and opposing shifts in large-scale brain organization.