Anesthesiology
September 30, 2010
Pierre Boveroux, Audrey Vanhaudenhuyse, Marie‐Aurélie Bruno et al.
645 citations
Propofol-induced unconsciousness is linked to decreased connectivity within frontoparietal networks (the default-mode and executive-control networks) and between the thalamus and these networks, with a negative correlation between thalamic and cortical activity emerging during unconsciousness. In contrast, connectivity in low-level sensory cortices (auditory and visual networks) is preserved, including their thalamocortical connections. Loss of consciousness is associated with a breakdown of cross-modal interactions between visual and auditory networks. These findings suggest that unconsciousness results from disrupted communication between sensory and higher-order frontoparietal cortices, preventing conscious perception.
Anesthesiology
June 27, 2005
Vincent Joly, Philippe Richebé, B. Guignard et al.
624 citations
A relatively large dose of the opioid remifentanil given during surgery triggers increased pain sensitivity after the operation, a phenomenon called secondary hyperalgesia. In a trial of 75 patients undergoing major abdominal surgery, those who received a high intraoperative dose of remifentanil (0.40 µg/kg/min) had greater pain sensitivity around the surgical wound and required more morphine for pain relief than patients who received a low dose (0.05 µg/kg/min). Adding a small dose of the drug ketamine during surgery prevented this heightened pain sensitivity, suggesting that remifentanil-induced hyperalgesia involves an N-methyl-d-aspartate pain-facilitator process. No significant differences were seen in overall pain scores, pressure pain thresholds, breathing tests, cognitive function, or side effects among the groups.
Anesthesiology
August 6, 2010
Edward F. Domino, David S. Warner
517 citations
CI-581, a derivative of phencyclidine, is an effective analgesic and anesthetic at doses of 1.0 to 2.0 mg per kilogram. Given intravenously, it acts within one minute and lasts 5 to 10 minutes depending on dose and individual variation. Repeat doses did not produce tachyphylaxis. Respiratory depression was slight and transient. Undesirable effects included hypertension, tachycardia, and psychic changes. Recovery from analgesia and coma typically occurred within 10 minutes, though electroencephalographic evidence indicated subjects were not fully normal for 1 to 2 hours. No liver or kidney toxicity was observed. The drug's effects resemble those of phencyclidine but are shorter-lasting, and it is proposed that the term 'dissociative anesthetic' describe the mental state it produces.
Anesthesiology
February 7, 2012
Robert D. Sanders, Giulio Tononi, Steven Laureys et al.
478 citations
Consciousness—subjective experience—persists during sleep and anesthesia, as evidenced by dreaming. A defining feature of dreaming is disconnection from the environment. Anesthesia aims to prevent the experience of surgery (connected consciousness) by inducing either unconsciousness or disconnection. The isolated forearm technique reveals that consciousness, connectedness, and responsiveness can uncouple during anesthesia; under clinical conditions, a median 37% of patients demonstrate connected consciousness. Potential neurobiological constructs explain this: during light anesthesia, subcortical mechanisms for spontaneous behavioral responsiveness are disabled, but information integration within the corticothalamic network continues producing consciousness, while unperturbed norepinephrinergic signaling maintains connectedness. These concepts emphasize the need for anesthetic regimens and depth-of-anesthesia monitors targeting mechanisms of consciousness, connectedness, and responsiveness.
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
January 1, 1998
Andrew t. Bowdle, Allen d. Radant, Deborah s. Cowley et al.
371 citations
Subanesthetic doses of ketamine produce a unique spectrum of subjective psychedelic effects in healthy volunteers. The relationship between steady-state venous plasma ketamine concentrations and the intensity of these effects is highly linear across the range of 50 to 200 ng/ml. Ketamine produced dose-related psychedelic effects, with linear regression coefficients for visual analog scale scores ranging from 0.93 to 0.99. Hallucinogen rating scale scores were similar to those found in a previous study with psychedelic doses of N,N-dimethyltryptamine, an illicit LSD-25-like drug.
Anesthesiology
July 1, 1991
Jean-Marc Malinovsky, A. Cozian, Jean-Yves Lepage et al.
244 citations
Intrathecal midazolam caused significant neurotoxicity in rabbits, as shown by both blood-brain barrier and light microscopy studies, and should be avoided in humans. Ketamine showed evidence of neurotoxicity in the blood-brain barrier study, though light microscopy found no significant differences compared to saline and lidocaine. Further studies of the solvent and different ketamine enantiomers are needed to establish the safety of intrathecal free ketamine in humans. Lidocaine and saline did not produce abnormal spinal cord lesions.
Anesthesiology
August 9, 2016
Vincent Bonhomme, Audrey Vanhaudenhuyse, Athena Demertzi et al.
206 citations
Ketamine alters consciousness by disrupting connectivity within and between specific resting-state brain networks, particularly the default mode network (DMn) and salience network (SALn), while leaving sensory and motor networks largely intact. In healthy volunteers given stepwise ketamine infusions until they lost responsiveness, DMn connectivity between the medial prefrontal cortex and other network regions decreased (from 0.20 to 0.07), and the normal anticorrelated activity between the DMn and sensory regions reversed (e.g., right sensory cortex shifted from -0.07 to 0.04). SALn connectivity was also suppressed but nonuniformly. These specific changes, including preserved sensory network connectivity, are shared with propofol-induced unconsciousness.
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.
Anesthesiology
August 13, 2012
Marieke Niesters, Najmeh Khalili‐mahani, Christian H. Martini et al.
141 citations
Low-dose S(+)-ketamine alters the brain's intrinsic large-scale functional connectivity, as measured by resting-state fMRI. In twelve healthy men, ketamine increased connectivity in the cerebellum and visual cortex while decreasing connectivity in auditory and somatosensory networks, including regions involved in pain sensing and affective processing such as the amygdala, insula, and anterior cingulate cortex. Pain-related connectivity changes occurred in areas responsible for descending pain inhibition, including the anterior cingulate cortex, insula, orbitofrontal cortex, and brainstem. These connectivity changes correspond to ketamine's known effects on analgesia, psychedelic experiences, and other side effects.
Anesthesiology
September 4, 2020
Jacob Gitlin, Shubham Chamadia, J. Locascio et al.
48 citations
Ketamine's pain-relieving effects are not solely due to its dissociative properties. In an open-label study, 15 healthy adults received 2 mg/kg of ketamine, with midazolam given later to reduce dissociation. Statistical models showed that dissociation and pain intensity followed similar time courses, but when dissociation scores were added to the pain model, dissociation did not account for the pain relief. This indicates that ketamine's analgesic and dissociative effects are independent, suggesting ketamine can be used to study pain circuits separate from those involved in dissociation.
Anesthesiology
February 21, 2022
Erik Olofsen, Jasper Kamp, Thomas K. Henthorn et al.
33 citations
Ketamine produces both pain relief (analgesia) and psychedelic effects, and these two effects are linked, possibly because dissociation generates analgesia. In healthy male volunteers receiving escalating doses of S-ketamine and racemic ketamine, the concentration-effect relationship and the speed of onset and offset were the same for both antinociception and altered external perception. S-ketamine had a potency (C50) of 0.51 nmol/ml and a blood-effect site equilibration half-life of 8.3 minutes. R-ketamine did not contribute to either effect, while S-norketamine had a small antagonistic effect. The authors suggest further studies are needed to explore brain connectivity underlying these effects.
Anesthesiology
October 1, 2023
Akash Goel, Yeshith Rai, Shayan Sivadas et al.
29 citations
Chronic pain affects about 1.5 billion people worldwide. Current treatments like opioids and non-opioid drugs can cause side effects, addiction, or fail to relieve pain. Psychedelics such as LSD and psilocybin may alter pain perception through serotonin receptor activation, anti-inflammatory effects, and synaptic remodeling. This scoping review identified 21 human studies on psychedelics for pain. Few clinical trials exist, and sample sizes are small, limiting clinical use. Overall, psychedelics show promise for analgesia in certain headache disorders and cancer pain. Future research should examine combining psychotherapy with psychedelics for chronic pain.
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.
Anesthesiology
August 1, 2024
Connor T A Brenna, Benjamin I Goldstein, Carlos A Zarate et al.
19 citations
Anesthetic drugs such as ketamine, nitrous oxide, propofol, and isoflurane show rapid and sustained antidepressant properties, positioning anesthesiologists at a new frontier in treating neuropsychiatric disorders. This article reviews these drugs as novel antidepressants and identifies future candidates for depression treatment. The authors call for collaboration between anesthesiologists and psychiatrists to repurpose anesthetic drugs as antidepressants and address mood disorders in surgical patients.
Anesthesiology
February 6, 2020
Andria Pelentritou, Levin Kuhlmann, John Cormack et al.
15 citations
Xenon and nitrous oxide produce different patterns of brain oscillatory power changes, depending on the gas and the recording method. Xenon increased low-frequency delta and theta power only at loss of responsiveness (delta: 208.3%, theta: 107.4% in MEG; delta: 260.3%, theta: 116.3% in EEG). Nitrous oxide increased high-frequency gamma power (low gamma: 46.3%, high gamma: 45.7% in MEG) and reduced frontal alpha power at 0.75 MACawake in MEG (44.4% reduction) and at 0.50 MACawake in EEG (44.0% reduction). The findings show no clear universal features of action for these two gaseous anesthetics, and differences between MEG and EEG must be considered for accurate brain state monitoring during anesthesia.
Anesthesiology
May 1, 2024
Zhenhu Liang, Bo Tang, Yu Chang et al.
13 citations
Two new measures of EEG microstate complexity—type I, quantifying randomness, and type II, quantifying fluctuation complexity—track anesthetic-induced unconsciousness independently of the drug used (propofol or esketamine). In 20 patients, type I complexity increased from wakefulness to unconsciousness and decreased upon recovery, while type II complexity showed the opposite pattern. Both measures changed significantly under both anesthetics, suggesting they reflect the state of consciousness rather than the specific drug. These complexity measures may serve as state-related neural correlates of consciousness during general 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.
Anesthesiology
June 1, 2024
George A Mashour, UnCheol Lee, Dinesh Pal et al.
8 citations
Near-death experiences have been reported since antiquity and often involve perceptions of light, interactions with entities, and life recall. After in-hospital cardiac arrest, such experiences occur in 10 to 20% of cases. Recent neurophysiologic evidence suggests a surge of gamma oscillations and increased cortical connectivity following cardiac and respiratory arrest, offering a biological basis for this conscious experience.
Anesthesiology
December 1, 2022
T. Andrew Bowdle, Nathan Sackett, Rick Strassman et al.
5 citations
The authors argue that the term "dissociative" is outdated and imprecise for describing the subjective effects of ketamine and related drugs. Originally coined in 1966 to describe feelings of being in outer space or lacking limbs, the term does not capture the full range of psychedelic experiences measured by modern rating scales like the Bowdle Visual Analogue Scale and Hallucinogen Rating Scale. The authors suggest that drugs such as phencyclidine, dextromethorphan, salvinorin A, and nitrous oxide—often grouped as "dissociative anesthetics"—produce subjective effects that are not identical to each other and can resemble those of classic psychedelics like dimethyltryptamine or psilocybin. They recommend describing these drugs primarily by their mechanism of action, such as "the NMDA antagonist ketamine," rather than by the term dissociative.
Anesthesiology
September 12, 2022
Albert Dahan, Erik Olofsen, Thomas K. Henthorn et al.
3 citations
The authors respond to a critique about how to describe mind-altering drugs like ketamine, psilocybin, and cannabis. They argue that terms like "dissociative" are inadequate because these drugs produce diverse symptoms beyond disconnection from reality. They propose "psychoplastogen" as a better term, focusing on the shared mechanism of promoting rapid neural plasticity and rewiring of brain circuits, which underlies therapeutic effects such as antidepressant and pain relief actions. This term avoids the limitations of describing subjective experiences and instead highlights the neurobiological mechanism responsible for healing.
Anesthesiology
September 18, 2020
B. Heifets
3 citations
Ketamine has many properties—analgesic, antidepressant, dissociative anesthetic, and others—making it hard to target for specific clinical uses. In a study of 15 healthy adults, Gitlin et al. tested whether ketamine's pain-relieving and dissociative effects are linked. Participants received a single anesthetic dose of ketamine (2 mg/kg) and rated dissociation and pain from a standardized pneumatic cuff stimulus. Using a statistical method called backward elimination, the authors found that dissociation scores did not predict pain scores, suggesting the two effects arise from independent mechanisms. The study also confirmed that midazolam reduced dissociation without affecting analgesia.
Anesthesiology
April 1, 1982
J. F. van Poorten, Rudolf Stienstra, B Dworacek et al.
3 citations
No Summary
Anesthesiology
May 21, 2014
Rafael G. Dos Santos
1 citation
A commentary critiques a prior article on psychedelic research, arguing it underrepresents the role of glutamate in psychedelic neurochemistry and incorrectly claims that psilocybin is the only classic psychedelic studied with human neuroimaging. The commentary notes that head-twitch behavior, a mouse proxy for human psychedelic action, depends on metabotropic glutamate 2 receptors co-expressed with 5-HT2A receptors. It also lists human neuroimaging studies of mescaline, dimethyltryptamine, and ayahuasca. The commentary raises unresolved questions about discrepancies between intravenous psilocybin studies showing decreased cerebral blood flow and oral psilocybin studies showing increased glucose metabolism.
Anesthesiology
February 26, 2021
D. Pal, G. Mashour
Cortical acetylcholine concentration tracks with the capacity for conscious experience: high during wakefulness, low during slow-wave sleep, and high again during REM sleep when dreaming occurs. General anesthetics produce parallel changes—GABAergic drugs like propofol and sevoflurane lower acetylcholine and reduce the probability of experience, while non-GABAergic drugs like ketamine and nitrous oxide raise acetylcholine and increase the likelihood of dreams or hallucinations. Interventions that raise brain acetylcholine reverse anesthetic traits or reduce potency in humans and rodents, whereas lesions of cholinergic neurons in the basal forebrain reduce anesthetic requirements for isoflurane and propofol.