Pet Scanning and Propofol
Action
Positron
Emission Tomography (PET) and functional Magnetic Resonnance Imaging (fMRI)
allow researchers to study brain function in vivo. Those techniques are used to
refine our understanding of the nature of anesthetic effects as well as of the
influence of anesthetic drugs on sensory and pain transmission.
How they work.
PET.
PET uses a combination of scintigraphic and computerized tomography
techniques. A biological compound labeled with a radioactive tracer (11C,
13N, 15O, 18F) is injected into a subject so
that its distribution in the target tissue can be determined. Depending on the
information desired, a variety of compounds can be labeled. For functional
brain studies, 15O labeled water is often used for determination of
regional Cerebral Blood Flow (rCBF) based on the assumption that changes in
rCBF are coupled with those of neuronal activity. Cerebral metabolic rate
studies are performed with labeled glucose or oxygen. It is also possible to
study neurotransmission by looking at the displacement of a labeled ligand from
its binding sites 1.
For example, 11C benztropine, an M1 and M2 non-specific
antagonist, is used by our group to study cholinergic muscarinic transmission
under anesthesia.
PET has been used for more than a decade for localization of human
cognitive operations 2.
The basis of PET studies is to submit a group of individuals to a series of
different conditions and to statistically compare the images to determine the
physiologic changes induced by a given condition. Examples of conditions are:
increasingly painful stimuli, increasing levels of drug sedation, or a more
complex pattern mixing painful stimuli at increasing levels of sedation.
fMRI.
fMRI uses a different principle.
Again, the basis of the studies is to compare changes in brain activation
induced between conditions in a strictly controlled experimental environment,
but there is no need for radioactive tracers, and the temporal resolution is
much better than with PET.
Brain imaging and Anesthesia.
Brain imaging offers unique possibilities for improving our knowledge of
anesthetic effects. Anesthesia induces a host of dose-specific and controllable
changes in CNS function. Our knowledge of propofol pharmacology and the
availability of powerful tools to achieve and maintain stable drug
concentrations allow us to use propofol as a prototypical anesthetic drug and
as modulators of consciousness. Stable levels, or conditions in the brain
imaging vocabulary, can be obtained that correspond to specific levels of
sedation. Dose specific changes in brain activity can be measured, and the
neurophysiological correlates of the regional changes can be explored. Brain
imaging allows us to have a systems approach to the investigation of mechanisms
of anesthesia based on the premise that, propofol, and by extension anesthetic
drugs, possibly has a dose-dependant effect on specific neural systems.
PET studies on propofol and regional cerebral effects.
Michael Alkire and his group (U.C. Irvine) have done a series of
propofol studies in human volunteers using 18fluorodeoxyglucose
(FDG). They studied the glucose metabolic rate in human volunteers3 and showed that it was not uniform. Cortical metabolism was depressed
more than sub-cortical and marked differences in regional cortical changes were
seen. In another study, they correlated EEG changes with the cerebral metabolic
reduction caused by propofol and isoflurane and proposed that a physiologic
link exists between those variables.
Our group has studied the effects of propofol on the CNS using PET. In a
first study, we have determined the effect of different levels of propofol
sedation, from light sedation to unconsciousness, on rCBF using 15H2O.
We found a significant decrease in rCBF of the thalamus, the orbito-frontal
cortices, and a large area of the medial parieto-occipital cortex extending
bilaterally to the parieto-occipital sulcus area4.
These anatomical sites are involved in the control of consciousness5 and
in various integrative and associative tasks. In particular, given the
importance of the thalamic function in conscious processes, this study, as well
as others show that “the level of functional thalamic activity occurring in a
brain during anesthesia is likely to be related in some manner to a person’s
level of consciousness”[a].
These results support the hypothesis that propofol has regional effects and
that certain brain structures might have a specific sensitivity to anesthetic
effect.
The neural pathways for conducting and perceiving pain and vibro-tactile
stimulation are well known and their activation following a stimulus can be
clearly and accurately shown using PET 6; 7. It is the very nature of anesthesia to alter the perception of
external stimuli thus allowing the performance of noxious operations but very
little is known on the exact mechanism by which such a disruption of neural
conduction happens. Is the stimulus blocked at the level of the dorsal horn,
the thalamus, the primary or secondary sensory cortex? Are we only modulating
the associative and affective functions related to pain perception? Do these
areas of the CNS show a dose-dependant sensitivity to anesthetics?
To try answering those questions, we have conducted a study on the
influence of the level of propofol sedation on vibro-tactile stimulation.
Volunteers were submitted to increasing target concentrations of propofol and
presented with standardized vibratory stimuli. We found a significant decrease
in activation of the primary sensory cortex at very low sedative doses of
propofol (0.5 mg·ml-1). A more profound effect is seen at higher levels of
sedation, with an almost complete abolition of activation at in the thalamus
when pharmacological unconsciousness is reached. This suggests that even when a
patient in only mildly sedated, a rather significant effect on cortical activation
might explain a relative indifference to external tactile stimuli 8.
PET allows us to explore another aspect of propofol action related to
neurotransmission. There are reports in the literature of reversal of
anesthetic effects with physostigmine, an anticholinesterase drug that crosses
the blood-brain barrier. In fact Antilirium® has been used for years to “speed
up awakening”. It is also common knowledge that scopolamine, an antimuscarinic
drug also crossing the blood-brain barrier induces sedation and potentiates
anesthetic effect. These facts, coupled with the extensive knowledge on the
modulatory effect of the central cholinergic system on sleep-wake states,
suggest that the central muscarinic system has a role to play in the generation
of anesthetic effect 9. We have used 11C-Benztropine, a non-specific M1 and M2
antagonist, to study muscarinic receptor occupancy during propofol-induced
unconsciousness. Preliminary results show an increase in benztropine binding
(reflecting a decrease in acetyl choline binding) under anesthesia in areas
rich in M1 receptors.
Conclusion:
Brain imaging is a window on the working brain. It offers tremendous
possibilities for understanding the neural processes involved in all aspects of
consciousness. Data from research in this field in the past 5 years suggest
that anesthetics are not simply general depressant of brain activity, but
rather act on specific structures of the CNS in a dose-dependant fashion.
1. Saha
GB, MacIntyre WJ, Go RT: Radiopharmaceuticals for brain imaging. Seminars in Nuclear Medicine 24:324-349,
1994
2. Posner
MI, Petersen SE, Fox PT, Raichle ME: Localization of cognitive operations in
the human brain. Science 240:1627-1631,
1988
3. Alkire
MT, Haier RJ, Barker SJ, Shah NK, Wu JC, Kao J: Cerebral metabolism during
propofol anesthesia in humans studied with positron emission tomography. Anesthesiology 82:393-403, 1995
4. Fiset
P, Paus T, Daloze T, Plourde G, Meuret P, Bonhomme V, Hajj-Ali N, Backman SB,
Evans AC: Brain mechanisms of propofol-induced loss of consciousness in humans:
a Positron Emission Tomography study.
Journal of neuroscience 19:5506-5513, 1999
5. Alkire
MT, Haier RJ, Fallon JH: Toward a unified theory of narcosis: brain imaging
evidence for a thalamocortical switch as the neurrophysiologic basis of
anesthetic-induced unconsciousness.
Consciousness and Cognition 9:370-386, 2000
6. Coghill
RC, Talbot JD, Evans AC, Meyer E, Gjedde A, Bushnell MC, Duncan GH: Distributed
processing of pain and vibration by the human brain. Journal of neuroscience 14:4095-4108, 1994
7. Talbot
JD, Marret S, Evans AC, Meyer E, Bushnell MC, Duncan GH: Multiple
representations of pain in human cerebral cortex. Science 251:1355-1357, 1991
8. Bonhomme
V, Fiset P, Meuret P, Backman SB, Plourde G, Paus T, Bushnell C, Evans A:
Effect of propofol-induced general anesthesia on changes in regional cerebral
blood flow elicited by vibrotactile stimulation: a positron emission tomography
(PET) study. Journal of Neurophysiology
Accepted:2000
9. Meuret
P, Backman SB, Bonhomme V, Plourde G, Fiset P: Physostigmine reverses
propofol-induced unconsciousness and attenuation of the auditory steady state
response and bispectral index in human volunteers. Anesthesiology 93:708-717, 2000