Anesthesia Mechanisms

Principal Investigator

Adjunct Professor (Docent) Harry Scheinin (E-mail: harry.scheinin(at)utu.fi)

Investigators

Figure1_mod
Part of the ”Anesthesia Mechanisms” group with our US collaborator in the HR+ PET scanner room. From left to right: Michael Alkire (UCI, CA), Harry Scheinin, Anu Maksimow, Jaakko Långsjö, Kimmo Kaskinoro and Satu Jääskeläinen.
Riku Aantaa (Docent, senior researcher)
Nora Hagelberg (Docent, senior researcher)
Satu Jääskeläinen (Professor, senior researcher)
Kaike Kaisti (Dr, post-doc)
Kimmo Kaskinoro (MD, doctoral student)
Ruut Laitio (Dr, post-doc)
Jaakko Långsjö (Dr, post-doc)
Anu Maksimow (Dr, post-doc)
Mika Mäenpää (MD, doctoral student)
Elina Salmi (Dr, post-doc)

Aims of the project

· To reveal the effects of different anesthetic drugs and their combinations on cerebral blood flow and metabolism

· To explore the neural correlates of human consciousness

·To reveal anesthesia mechanisms and to help in developing new EEG-based methods to monitor the depth of drug-induced anesthesia/hypnosis in humans

·To explore the effects of anesthetic drugs on the autonomic nervous system and especially on heart rate variability

·To study the neurotransmitter mechanisms of experimental and clinical pain

Main results of previous studies
The “Anesthesia Mechanisms” group of Turku PET Centre has studied the effects of various anesthetics and their combinations on regional cerebral blood flow, brain metabolism and electroencephalography (EEG) since the late 1990’s. The main focus of these studies has been “neuroanesthesiological”, i.e., on the systematic exploration of the effects of general anesthesia on brain homeostasis, especially the coupling between regional blood flow and metabolism using positron emission tomography (PET). Such knowledge is important in optimizing anesthesia regimens for compromised brain and in developing new anesthetic drugs and treatments.

The following anesthetic agents have been studied: Propofol, sevoflurane, adjunct nitrous oxide, ketamine, S-ketamine, dexmedetomidine and xenon. We have also carried out PET studies to reveal the GABAergic mechanisms of different anesthetic agents and the role of dopamine receptors in pain and opioid effects. The description of different projects and their main results can be found below under “Completed theses”.

figure2
Drawings of a ventilator add-on unit to a Sevo 900C ventilator that enables complex functional brain studies using labeled oxygen and carbon monoxide gases as PET tracers. The unit manages both steady-state and bolus inhalations, and the latter can be manually initiated using a remote trigger. The unit can be operated during both spontaneous pressure support breathing and volume-controlled ventilation. It supports the standard safety features and alarms of the ventilator and includes an overflow valve in the bolus reservoir.
Figure3_mod
A study subject anesthetized with xenon during PET scanning. The closed-circuit Physioflex ventilator is on the left and GE Datex-Ohmeda S/5 anesthesia monitor on the right. The subject was endotracheally intubated during the experiment.

Current research activities and recent results

Unconsciousness induced by general anesthesia constitutes an excellent platform to study the neural basis of consciousness. Healthy volunteers were put under anesthesia in a brain scanner using either dexmedetomidine or propofol in our Academy of Finland funded “Neurophilosophy of Consciousness” project. Dexmedetomidine is used as a sedative in the intensive care unit setting and propofol is widely used for induction and maintenance of general anesthesia. Dexmedetomidine-induced unconsciousness has a close resemblance to normal physiological sleep, as it can be reversed with mild physical stimulation or loud voices without requiring any change in the dosing of the drug. This unique property was critical to the study design, as it enabled to separate the brain activity changes associated with the changing level of consciousness from the drug-related effects on the brain. The state-related changes in brain activity were imaged with radiowater PET.

The emergence of consciousness, as assessed with a motor response to a spoken command, was associated with the activation of a core network involving subcortical and limbic regions that became functionally coupled with parts of frontal and inferior parietal cortices upon awakening from dexmedetomidine-induced unconsciousness. This network thus enabled the subjective awareness of the external world and the capacity to behaviorally express the contents of consciousness through voluntary responses. Interestingly, the same deep brain structures, i.e. the brain stem, thalamus, hypothalamus and the anterior cingulate cortex, were activated also upon emergence from propofol anesthesia, suggesting a common, drug-independent mechanism of arousal. For both drugs, activations seen upon regaining consciousness were thus mostly localized in deep, phylogenetically old brain structures rather than in the neocortex.

Figure4
Returning from oblivion – Imaging the neural core of consciousness (Långsjö et al, J Neurosci 2012). Positron emission tomography (PET) findings showing that the emergence of consciousness after anesthesia is associated with activation of deep, phylogenetically old brain structures rather than the neocortex. Left: Sagittal (top) and axial (bottom) sections showing activation in the anterior cingulate cortex (i), thalamus (ii) and the brainstem (iii) locus coeruleus/parabrachial area overlaid on magnetic resonance image (MRI) slices. Right: Cortical renderings showing no evident activations.
Awakening from anesthesia is often associated with an initial phase of delirious struggle before the full restoration of awareness and orientation to one’s surroundings. Our results imply why: primitive consciousness emerges first. Because current depth-of-anesthesia monitoring technology is based on cortical electroencephalography (EEG) measurement (i.e., measuring electrical signals on the surface of the scalp that arise from the brain’s cortical surface), these results help to explain why these devices fail in differentiating the conscious and unconscious states and why patient awareness during general anesthesia may not always be detected. The results may also have broader implications. The demonstration of which brain mechanisms are involved in the emergence of the conscious state is an important step forward in the scientific explanation of consciousness.

We are currently also analyzing brain connectivity changes related to loss and regaining consciousness using quantitative EEG and a novel directional connectivity measure, renormalized partial directed coherence (rPDC).

Collaboration

· Professor Michael Alkire, University of California, Irvine, CA, USA.

· Professor Jarmo Hietala, University of Turku, Turku, Finland.

· Professor Pasi Karjalainen, University of Eastern Finland, Kuopio, Finland.

· Professor Mervyn Maze, University of California, San Francisco, San Francisco, CA, USA.

· Professor Antti Pertovaara, University of Helsinki, Helsinki, Finland.

· Professor Antti Revonsuo, University of Turku, Turku Finland and University of Skövde, Skövde, Sweden.

· Professor Juha Rinne, University of Turku, Turku, Finland.

· Professor Mika Scheinin, University of Turku, Turku, Finland.

· Ph.D. Minna Silfverhuth, University of Oulu, Oulu, Finland.

External funding

· Academy of Finland (Research Programme on Neuroscience, project No. 8111818)

· Turku University Hospital (EVO grant 13323)

· Sigrid Jusélius Foundation

· Instrumentarium Science Foundation

· AGA AB Medicinska Forskningsfond

· Paulo Foundation

Completed theses

Nora Hagelberg:
Role of dopamine receptors in pain and opioid effects. Positron emission tomography studies in healthy subjects and patients with chronic orofacial pain. University of Turku, 2004.

Kaike Kaisti:
The effects of sevoflurane, propofol and nitrous oxide on regional cerebral blood flow, oxygen consumption and blood volume. Positron emission tomography and EEG studies on healthy subjects. University of Turku, 2004.

Jaakko Långsjö:
The effects of ketamine on cerebral blood flow and metabolism. Positron emission tomography studies on healthy male subjects. University of Turku, 2005.

Anu Maksimow:
The effects of anesthesia and sedation on EEG spectral entropy and regional cerebral blood flow. Positron emission tomography and EEG studies on healthy male subjects. University of Turku, 2006.

Elina Salmi:
The effects of general anesthetics on gabaergic neurotransmission. Positron emission tomography studies in healthy subjects. University of Turku, 2007.

Ruut Laitio:
The effects of xenon anesthesia on the central nervous system. Positron emission tomography and EEG studies on healthy subjects. University of Turku, 2007.

Five selected publications

Långsjö JW, Alkire MT, Kaskinoro K, Hayama H, Maksimow A, Kaisti KK, Aalto S, Aantaa R, Jääskeläinen SK, Revonsuo A, Scheinin H. Returning from oblivion: imaging the neural core of consciousness; J Neurosci 2012;32:4935-4943.

Kaskinoro K, Maksimow A, Långsjö J, Aantaa R, Jääskeläinen S, Kaisti K, Särkelä M, Scheinin H. Wide inter-individual variability of bispectral index and spectral entropy at loss of consciousness during increasing concentrations of dexmedetomidine, propofol, and sevoflurane. Br J Anaesth 2011;107:573-580.

Laitio RM, Kaisti KK, Långsjö JW, Aalto S, Salmi E, Maksimow A, Aantaa, R, Oikonen V, Sipilä H, Parkkola R, Scheinin H. Effects of xenon anesthesia on cerebral blood flow in humans – a positron emission tomography study. Anesthesiology 2007;106:1128-1133.

Salmi E, Kaisti KK, Metsähonkala L, Oikonen V, Aalto S, Någren K, Hinkka S, Hietala J, Korpi ER, Scheinin H. Sevoflurane and propofol increase 11C-flumazenil binding to gamma-aminobutyric acidA receptors in humans. Anesth Analg 2004;99:1420-1426.

Kaisti KK, Långsjö JW, Aalto S, Oikonen V, Sipilä H, Teräs M, Hinkka S, Metsähonkala L, Scheinin H. Effects of sevoflurane, propofol, and adjunct nitrous oxide on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology 2003;99:603-613.

Click here for the complete list of publications from Anesthesia Mechanisms group.