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.

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.

64-channel EEG will be recorded and analyzed using time domain, spectral domain, functional connectivity, directed/effective connectivity and graph theoretical analysis methods.

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.

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.

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.

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.

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.

Inclusion Criteria: Male Age 18-30 years Good general health i.e. American Society of Anesthesiologists (ASA) physical status I Fluent in Finnish language Right handedness Written informed consent Good sleep quality Exclusion Criteria: Chronic medication History of alcohol and/or drug abuse Strong susceptibility for allergic reactions Serious nausea in connection with previous anesthesia Strong susceptibility for nausea Any use of drugs or alcohol during the 48 hours preceding anesthesia Use of caffeine products 10-12 hours prior the study Smoking Clinically significant previous cardiac arrhythmia / cardiac conduction impairment Clinically significant abnormality in prestudy laboratory tests Positive result in the drug screening test Blood donation within 90 days prior to the study Participation in any medical study with an experimental drug or device during the preceding 60 days The study subject has undergone a prior PET or SPECT study Any contraindication to magnetic resonance imaging (MRI) Hearing impairment Detected unsuitability based on MRI scanning results if available before the PET scanning Sleep disorder or severe sleep problem

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.