Anesthesiology
May 22, 2013
UnCheol Lee, Seungwoo Ku, Gyu‐jeong Noh et al.
436 citations
Ketamine, like propofol and sevoflurane, inhibits feedback (anterior-to-posterior) connectivity between frontal and parietal brain regions after loss of consciousness, while preserving feedforward (posterior-to-anterior) connectivity. In 30 surgical patients given intravenous ketamine (2 mg/kg), electroencephalography showed that feedback connectivity gradually diminished and was significantly reduced after loss of consciousness (mean baseline 0.0074 vs. anesthesia 0.0055). Feedforward connectivity remained unchanged. Ketamine reduced alpha power and increased gamma power, unlike propofol and sevoflurane. Despite molecular and neurophysiologic differences, diverse anesthetics disrupt frontal-parietal communication, suggesting that directional connectivity analysis could provide a common metric for general anesthesia.
Anesthesiology
September 7, 2013
Heonsoo Lee, George A. Mashour, Gyu‐jeong Noh et al.
153 citations
General anesthesia with propofol reconfigures the brain's functional network hub structure and reverses the phase relationship between frontal and parietal regions. Using graph theoretical analysis of 21-channel electroencephalogram data from 10 volunteers, the study found that network topology—not connection strength—correlates with states of consciousness. After propofol administration, average path length, clustering coefficient, and modularity increased, long-range connections were disrupted, and hub node strength decreased. The primary hub shifted from parietal to frontal regions. The phase lead of frontal to parietal areas in the alpha frequency band (8-13 Hz) during wakefulness reversed direction after propofol and returned during recovery. Changes in network topology may be the primary mechanism for loss of frontal to parietal feedback during anesthesia.
Proceedings of the National Academy of Sciences
June 10, 2013
George A. Mashour, Michael T. Alkire
148 citations
Consciousness likely emerged early in vertebrate evolution, as the basic neural mechanisms supporting it are ancient and highly conserved across species. The stepwise emergence from general anesthesia can serve as a reproducible model to study consciousness across species. The neurobiological structure of the vertebrate central nervous system is evolutionarily ancient, and the neurophysiologic mechanisms supporting human consciousness are found at the earliest points of vertebrate brain evolution. Differences between species in the ability to experience the world are of degree, not kind, supporting Darwin's insight and the Cambridge Declaration on Consciousness in Non-Human Animals.
PLoS Computational Biology
April 14, 2015
Joon-Young Moon, UnCheol Lee, Stefanie Blain‐moraes et al.
143 citations
Efficient brain networks balance global integration with functional specialization, but how global topology, local node dynamics, and information flow relate has been unclear. Using analytical solutions of oscillator models, computational simulations on model and anatomical brain networks, and high-density electroencephalography from conscious and anesthetized humans, the authors demonstrate that network nodes with more connections (higher degree) have larger amplitudes and are directional targets (phase lag) rather than sources (phase lead). This degree–directionality relationship appears to be a fundamental network property with direct applicability to brain function. Changes in directionality patterns across states of human consciousness are driven by alterations in brain network topology.
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
September 19, 2006
George A. Mashour
135 citations
The nature and mechanism of human consciousness is becoming a central scientific and philosophical question. Once disregarded, the study of consciousness has regained legitimacy. Research on consciousness and general anesthesia is converging. This article introduces the study of consciousness, describes neural correlates that may be targets of anesthetics, and proposes an integrated approach to the science of consciousness and anesthesia.
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.
British Journal of Anaesthesia
April 13, 2018
Phillip E. Vlisides, Tarik Bel‐bahar, Amanda Nelson et al.
117 citations
Subanaesthetic doses of ketamine produce altered states of consciousness dominated by dissociative experiences such as disembodiment and ego transcendence, along with sensory disturbances. These subjective effects occur alongside a broad decrease in low-frequency brain electrical activity, with the largest reductions in alpha power (8–12 Hz) in parietal and occipital regions. Specific decreases in alpha power were identified in the precuneus and temporal-parietal junction, brain areas involved in multisensory integration, body representation, and consciousness. The findings suggest that modulation of these temporal-parietal loci may be a candidate mechanism for ketamine's psychoactive effects.
NeuroImage
April 5, 2019
Duan Li, George A. Mashour
103 citations
Ketamine produces dose-dependent effects on the brain's spatiotemporal complexity. At a subanesthetic dose, ketamine elevates complexity relative to baseline, while an anesthetic dose initially causes alternating low and high complexity levels before stabilizing at a high level comparable to baseline. These findings reveal that ketamine-induced state transitions blend features of general anesthesia, normal consciousness, and altered states, advancing understanding of its pharmacological and neurophysiological properties.
PLoS Computational Biology
August 30, 2018
Hyoungkyu Kim, Joon-Young Moon, George A. Mashour et al.
79 citations
Hysteresis—the difference between the forward and reverse paths of state transitions—occurs as people lose and regain consciousness. Analyzing high-density EEG from healthy volunteers given sevoflurane or ketamine, the authors found that functional brain networks exhibit hysteresis during these transitions. The principle of explosive synchronization, which governs abrupt state shifts in many complex networks, also explains hysteresis in the brain. More potent anesthetics produce larger hysteresis; a broader range of EEG frequencies hastens the loss of consciousness but delays its return; connectivity shows greater hysteresis than EEG power; and network structure and strength reconfigure differently during loss versus recovery. These results indicate that hysteresis in conscious state transitions is a generic network feature, potentially allowing prediction and modulation of such transitions.
Frontiers in Human Neuroscience
March 18, 2021
Emma R. Huels, Hyoungkyu Kim, UnCheol Lee et al.
51 citations
Shamanic practitioners in trance show brain changes that overlap with but are distinct from those caused by psychedelic drugs. In 24 practitioners and 24 controls, EEG recordings during shamanic drumming revealed increased gamma power linked to visual changes, decreased low alpha and increased low beta connectivity, reduced gamma-band signal diversity tied to insightfulness, and increased criticality in beta and gamma bands correlating with complex imagery. Practitioners' altered-state scores matched or exceeded those of people on psychedelics. The findings indicate that shamanic trance and psychedelic states share some phenomenal features but produce unique neural signatures.
Frontiers in Systems Neuroscience
March 23, 2017
Duan Li, Viviane S. Hambrecht‐Wiedbusch, George A. Mashour
33 citations
High-frequency gamma connectivity across the cortex is present during consciousness and depressed during unconsciousness. Subanesthetic ketamine (25 mg/kg) administered during isoflurane anesthesia accelerates recovery upon discontinuation of the primary anesthetic and increases gamma power during emergence. In rodents, ketamine reduced emergence time by 44%. During accelerated emergence, frontal-parietal coherence and normalized symbolic transfer entropy in high-frequency gamma bandwidth were increased compared with saline-treated controls. Surrogates of cortical information exchange in high-frequency gamma are increased in association with accelerated recovery from anesthesia, suggesting a functional significance of high-gamma information transfer in consciousness.
Anesthesiology
March 18, 2022
George A. Mashour
29 citations
Ketamine produces analgesia, psychedelic effects, and dissociation, but it is unclear whether these effects stem from a single mechanism or separate ones. An accompanying study by Olofsen et al. attempts to disentangle the antinociceptive (pain-relieving) and psychedelic properties of ketamine. The editorial discusses the drug's history and its varied uses as an anesthetic, analgesic, antidepressant, and psychotomimetic, questioning whether these psychoactive properties are reducible to a fundamental cause or represent dissociable traits with distinct mechanisms.
Scientific Reports
February 16, 2021
Catherine Duclos, Danielle Nadin, Yacine Mahdid et al.
28 citations
Three-node network motifs—recurring patterns of connections—reorganize in the brain during anesthetic-induced unconsciousness and recovery. In nine healthy volunteers undergoing a 3-hour anesthesia protocol, electroencephalography (EEG) recordings in the alpha band (8–13 Hz) showed that two specific motifs (motifs 1 and 5) changed their topology significantly between responsive and unresponsive states. Motif 1 consisted of long-range chain-like connections, while motif 5 comprised short-range loop-like connections. The topological reorganization of motif 5 preceded the return of responsiveness, and motif 1 accompanied it, suggesting these motifs may help reveal neural correlates of consciousness.
NeuroImage
January 7, 2022
Duan Li, Phillip E. Vlisides, George A. Mashour
24 citations
Spontaneous brain activity explores a repertoire of recurring spatial patterns, and the richness of this repertoire may reflect the capacity for consciousness. Ketamine, which has both psychedelic and anesthetic properties depending on dose, was used to examine brain dynamics across a continuum of consciousness. Analyzing EEG data from source-localized cortical activity, researchers identified frequency-specific spatial coactivation patterns. Ketamine anesthesia shifted brain states toward those with low spatial variability. Subanesthetic ketamine was associated with a richer repertoire of brain states, while anesthetic ketamine initially reduced repertoire richness, which then evolved to a level comparable to normal wakefulness before recovery of consciousness. These findings describe ketamine's modulation of cortical dynamics across spatial, temporal, and spectral dimensions.
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.
Frontiers in Pain Research
March 18, 2025
Jenna McAfee, Avinash Hosanagar, Vijay Tarnal et al.
18 citations
In a small open-label pilot trial, five people with fibromyalgia received two doses of psilocybin (15 mg and 25 mg) along with psychotherapy. The treatment was well-tolerated: there were temporary increases in blood pressure or heart rate during dosing that returned to normal, no serious adverse events, and four of five participants had short-lived headaches. One month after the second dose, participants reported large reductions in pain severity, pain interference, and sleep disturbance. One participant rated their symptoms as very much improved, two as much improved, and two as minimally improved. Recruitment stopped early due to generalizability concerns and changing FDA guidance, but the results suggest psilocybin-assisted therapy is safe for fibromyalgia and warrants larger trials.
bioRxiv (Cold Spring Harbor Laboratory)
October 23, 2023
Tyler G. Ekins, Isla Brooks, Sameer Kailasa et al.
17 citations
preprint
Classic psychedelic drugs, such as LSD and psilocybin, are thought to boost brain cell activity in the prefrontal cortex by activating serotonin 2A receptors. However, this research shows that these drugs actually suppress the intrinsic excitability of pyramidal neurons in a dose-dependent manner. The suppression is stronger when drugs are applied outside cells than inside, and it occurs through a previously unknown mechanism: enhancement of potassium M-current channels, independent of serotonin 2A receptor activation. Computer models reveal that M-current activation interacts with other mechanisms to reduce excitability and shorten working memory span. This suggests psychedelics may trigger widespread homeostatic adjustments that contribute to therapeutic benefits.
NeuroQuantology
September 4, 2007
George A. Mashour
17 citations
The cognitive binding problem asks how the brain combines its separate processing systems into a unified conscious experience. This essay examines proposed solutions, especially neural synchronization, and relates them to the relativity of simultaneity. It incorporates Kant's transcendental unity of apperception and transcendental aesthetic from the Critique of Pure Reason, leading to a broader consideration of consciousness and time, including non-temporal theories. The emerging field of quantum neurodynamics is discussed for its remarkable relationship to Kant. Finally, Kant's philosophy is used as a basis for a neurophilosophical method in consciousness research.
PLoS ONE
August 15, 2013
Jeongkyu Shin, George A. Mashour, Seungwoo Ku et al.
16 citations
General anesthesia rapidly alters brain network connectivity, and standard graph-theoretical methods that assume static networks are poorly suited to capture these changes. A new technique was introduced to track the temporal evolution of network modules. Multichannel EEG was recorded from 18 surgical patients anesthetized with propofol or sevoflurane. Networks were reconstructed by treating each EEG channel as a node and correlated activity between channels as a link. The frequency of subgraphs with a defined number of links was analyzed; subgraphs with high occurrence probability were called network "backbones." Constitutive, variable, and state-specific backbones were identified across consciousness, induction, maintenance, and recovery. This approach enables a granular, dynamic description of network evolution.
Frontiers in Systems Neuroscience
August 11, 2020
Michael A. Brito, Duan Li, George A. Mashour et al.
15 citations
Ketamine and propofol anesthesia both reduce cortical complexity, but in different frequency bands. Using Lempel-Ziv complexity (LZc) to analyze electroencephalographic data from rats, the study found that ketamine anesthesia significantly reduced complexity in the high gamma range (65–175 Hz), while propofol anesthesia reduced complexity in lower frequencies (0.5–55 Hz). During emergence from ketamine anesthesia, complexity increased in broadband and low-frequency ranges. After normalizing for spectral influences, the reductions during anesthesia remained significant, indicating they are genuine neurophysiological features. The findings suggest that reduced high gamma complexity is a specific marker of ketamine anesthesia.
Anesthesiology
September 21, 2013
Eduardo E. Icaza, George A. Mashour
11 citations
The neural mechanisms underlying the psychedelic experience remain poorly understood. A recent neuroimaging study found that psilocybin decreases cerebral blood flow and causes functional disconnections in the brain, a pattern surprisingly similar to that produced by general anesthetics. This article reviews historical instances of psychedelic experiences triggered by anesthetics and compares how these two drug classes produce altered states 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 Preprint Server
January 22, 2025
Emma R. Huels, Nicholas Kolbman, Christopher W. Fields et al.
4 citations
preprint
A serotonergic psychedelic, DOI, can reverse general anesthesia and restore wakefulness in rats, even while anesthetics like propofol or isoflurane continue to be delivered. Behavioral arousal was accompanied by recovery of high gamma functional connectivity and restoration of brain network structure. These effects were blocked by a 5-HT2A antagonist, volinanserin, and a non-psychedelic 5-HT2A agonist, lisuride, failed to produce similar results. This provides the first evidence of psychedelic-mediated reversal of general anesthesia and concurrent restoration of brain dynamics associated with normal wakefulness.