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| Name | Class |
|---|---|
| University of California, Irvine | OTHER |
| University of Michigan | OTHER |
| Yale University | OTHER |
| University of Helsinki |
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Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and electroencephalography (EEG) studies will be carried out to reveal the neural correlates of consciousness. Consciousness of the subjects will be manipulated with anesthetic agents dexmedetomidine, propofol, S-ketamine and sevoflurane. One-hundred-and-sixty (160) healthy male subjects will be recruited to receive EC50 concentration of the anesthetic (40 dexmedetomidine, 40 propofol, 20 S-ketamine, 40 sevoflurane) or placebo (20) while being imaged for cerebral metabolic rate of glucose (CMRglu). Also genetic, immunological and metabolomics samples will be taken and analysed to find possible genetic factors explaining the variability in drug response and to find chemical fingerprints of acute drug effect.
The explanation of consciousness poses one of the greatest challenges to science and philosophy in the 21st century. It remains unclear what consciousness is and how it emerges from brain activity. Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and electroencephalography (EEG) studies will be carried out to reveal the neural correlates of consciousness. Consciousness of the subjects will be manipulated with anesthetic agents dexmedetomidine acting through α2-agonism, with propofol and sevoflurane both mainly acting through the enhancement of gamma-aminobutyric acid (GABA) system, and with S-ketamine acting through N-methyl-D-aspartate (NMDA) receptor antagonism. One-hundred-and-sixty (160) healthy male subjects will be recruited to receive EC50 concentration of either dexmedetomidine, propofol, S-ketamine or sevoflurane, or placebo while being imaged for cerebral metabolic rate of glucose (CMRglu). 40 subjects will receive dexmedetomidine, 40 subjects propofol, 20 subjects S-ketamine, 40 subjects sevoflurane and 20 subjects will receive placebo. Also genetic, immunological and metabolomics samples will be taken and analysed to find possible genetic factors explaining the variability in drug response and to find possible immunological and chemical fingerprints of acute drug effect.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dexmedetomidine | Experimental | Intravenous dexmedetomidine using target controlled infusion. |
|
| Propofol | Experimental | Intravenous propofol using target controlled infusion. |
|
| S-ketamine | Experimental | Intravenous S-ketamine using target controlled infusion. |
|
| Sevoflurane | Experimental | Inhalational sevoflurane using target controlled inhalation. |
|
| Placebo | Placebo Comparator | Intravenous saline. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dexmedetomidine | Drug | Intravenous infusion |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Regional cerebral metabolism of glucose | Comparison of responsive and unresponsive subjects | 40 min |
| Measure | Description | Time Frame |
|---|---|---|
| EEG | 64-channel EEG will be recorded and analyzed using time domain, spectral domain, functional connectivity, directed/effective connectivity and graph theoretical analysis methods. | 1 hour |
| Immunological effects |
| Measure | Description | Time Frame |
|---|---|---|
| Drug concentration in plasma or end-tidal | 1 hour |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Harry Scheinin, MD | Turku PET Centre, University of Turku, Turku, Finland | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Turku PET Centre | Turku | FI-20521 | Finland |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22492049 | Background | Langsjo JW, Alkire MT, Kaskinoro K, Hayama H, Maksimow A, Kaisti KK, Aalto S, Aantaa R, Jaaskelainen SK, Revonsuo A, Scheinin H. Returning from oblivion: imaging the neural core of consciousness. J Neurosci. 2012 Apr 4;32(14):4935-43. doi: 10.1523/JNEUROSCI.4962-11.2012. | |
| 24025060 | Background | Langsjo JW, Revonsuo A, Scheinin H. Harnessing anesthesia and brain imaging for the study of human consciousness. Curr Pharm Des. 2014;20(26):4211-24. |
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| ID | Term |
|---|---|
| D014474 | Unconsciousness |
| ID | Term |
|---|---|
| D003244 | Consciousness Disorders |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D020927 | Dexmedetomidine |
| D015742 | Propofol |
| C000629870 | Esketamine |
| D000077149 | Sevoflurane |
| ID | Term |
|---|---|
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| OTHER |
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| Propofol | Drug | Intravenous infusion |
|
|
| S-ketamine | Drug | Intravenous infusion |
|
|
| Sevoflurane | Drug | Inhalation |
|
|
| Placebo | Drug | Intravenous infusion of saline (Ringer's Acetate) |
|
Blood samples will be draw at baseline (without drug), at the end of study drug administration and after PET scanning for the measurement of approximately 50 cytokines, chemokines and growth factors.
| 2 hours |
| Metabolomic effects | Blood samples will be drawn at baseline (without drug), at the end of drug administration and after PET scanning for the measurement of more than 200 serum measures, including lipoprotein subclass distribution and lipoprotein particle concentration, low molecular weight metabolites, such as amino acids, 3-hydroxybutyrate and creatinine, and detailed molecular information on serum lipids, including free and esterified cholesterol, sphingomyelin and fatty acid saturation. | 2 hours |
| Gene expression | Blood samples will be collected at baseline (without drug), at the end of drug administration and after PET scanning for the measurement of RNA expression using whole genome microarray-based, massively parallel sequencing or quantitative reverse-transcription polymerase chain reaction based methods. | 2 hours |
| Psychological well-being | Psychological well-being and ill-being will be measured with a battery of scientifically validated scales just before initiating the study session and at the end of the study session. | 2 hours |
| Dream report | After terminating PET imaging, a structured interview is immediately conducted to verify a recollection or absence of recollection of subjective experiences during possible loss of responsiveness. | 1 hour |
| 37588789 | Derived | Nummela A, Laaksonen L, Scheinin A, Kaisti K, Vahlberg T, Neuvonen M, Valli K, Revonsuo A, Perola M, Niemi M, Scheinin H, Laitio T. Circulating oxylipin and bile acid profiles of dexmedetomidine, propofol, sevoflurane, and S-ketamine: a randomised controlled trial using tandem mass spectrometry. BJA Open. 2022 Dec 12;4:100114. doi: 10.1016/j.bjao.2022.100114. eCollection 2022 Dec. |
| 34534172 | Derived | Nummela AJ, Laaksonen LT, Laitio TT, Kallionpaa RE, Langsjo JW, Scheinin JM, Vahlberg TJ, Koskela HT, Aittomaki V, Valli KJ, Revonsuo A, Niemi M, Perola M, Scheinin H. Effects of dexmedetomidine, propofol, sevoflurane and S-ketamine on the human metabolome: A randomised trial using nuclear magnetic resonance spectroscopy. Eur J Anaesthesiol. 2022 Jun 1;39(6):521-532. doi: 10.1097/EJA.0000000000001591. Epub 2021 Sep 22. |
| 29935583 | Derived | Laaksonen L, Kallioinen M, Langsjo J, Laitio T, Scheinin A, Scheinin J, Kaisti K, Maksimow A, Kallionpaa RE, Rajala V, Johansson J, Kantonen O, Nyman M, Siren S, Valli K, Revonsuo A, Solin O, Vahlberg T, Alkire M, Scheinin H. Comparative effects of dexmedetomidine, propofol, sevoflurane, and S-ketamine on regional cerebral glucose metabolism in humans: a positron emission tomography study. Br J Anaesth. 2018 Jul;121(1):281-290. doi: 10.1016/j.bja.2018.04.008. Epub 2018 May 8. |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010636 |
| Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D008738 | Methyl Ethers |
| D004987 | Ethers |
| D006845 | Hydrocarbons, Fluorinated |
| D006846 | Hydrocarbons, Halogenated |