The Neural Mechanisms of Anesthesia and Human Consciousness (Part 6)

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.

Study Overview

• Status: Completed
• Conditions: Unconsciousness; Anesthesia
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Propofol; Drug: S-ketamine; Drug: Sevoflurane; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 4

Contacts and Locations

Study Locations

• Finland
  • Turku, Finland, FI-20521
    • Turku PET Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 30 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Male
2. Age 18-30 years
3. Good general health i.e. American Society of Anesthesiologists (ASA) physical status I
4. Fluent in Finnish language
5. Right handedness
6. Written informed consent
7. Good sleep quality

Exclusion Criteria:

1. Chronic medication
2. History of alcohol and/or drug abuse
3. Strong susceptibility for allergic reactions
4. Serious nausea in connection with previous anesthesia
5. Strong susceptibility for nausea
6. Any use of drugs or alcohol during the 48 hours preceding anesthesia
7. Use of caffeine products 10-12 hours prior the study
8. Smoking
9. Clinically significant previous cardiac arrhythmia / cardiac conduction impairment
10. Clinically significant abnormality in prestudy laboratory tests
11. Positive result in the drug screening test
12. Blood donation within 90 days prior to the study
13. Participation in any medical study with an experimental drug or device during the preceding 60 days
14. The study subject has undergone a prior PET or SPECT study
15. Any contraindication to magnetic resonance imaging (MRI)
16. Hearing impairment
17. Detected unsuitability based on MRI scanning results if available before the PET scanning
18. Sleep disorder or severe sleep problem

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Dexmedetomidine; Intravenous dexmedetomidine using target controlled infusion.	Drug: Dexmedetomidine; Intravenous infusion; Other Names: Dexdor
EXPERIMENTAL: Propofol; Intravenous propofol using target controlled infusion.	Drug: Propofol; Intravenous infusion; Other Names: Propofol-Lipuro
EXPERIMENTAL: S-ketamine; Intravenous S-ketamine using target controlled infusion.	Drug: S-ketamine; Intravenous infusion; Other Names: Ketanest-S
EXPERIMENTAL: Sevoflurane; Inhalational sevoflurane using target controlled inhalation.	Drug: Sevoflurane; Inhalation; Other Names: Sevorane
PLACEBO_COMPARATOR: Placebo; Intravenous saline.	Drug: Placebo; Intravenous infusion of saline (Ringer's Acetate)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regional cerebral metabolism of glucose	Comparison of responsive and unresponsive subjects	40 min

Secondary Outcome Measures

Outcome Measure	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	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

Other Outcome Measures

Outcome Measure	Time Frame
Drug concentration in plasma or end-tidal	1 hour

Collaborators and Investigators

• Sponsor: University of Turku
• Collaborators: Yale University; University of Michigan; University of California, Irvine; University of Helsinki
• Investigators: Principal Investigator: Harry Scheinin, MD, Turku PET Centre, University of Turku, Turku, Finland

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (ACTUAL): March 13, 2017
• Study Completion (ACTUAL): March 13, 2017

Study Registration Dates

• First Submitted: November 25, 2015
• First Submitted That Met QC Criteria: December 3, 2015
• First Posted (ESTIMATE): December 8, 2015

Study Record Updates

• Last Update Posted (ACTUAL): March 27, 2017
• Last Update Submitted That Met QC Criteria: March 22, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Consciousness Disorders; Unconsciousness; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Analgesics, Non-Narcotic; Platelet Aggregation Inhibitors; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Psychotropic Drugs; Antidepressive Agents; Hypnotics and Sedatives; Anesthetics, Inhalation; Ketamine; Propofol; Dexmedetomidine; Sevoflurane; Esketamine
• Other Study ID Numbers: LOC-2016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO