1Department of Anesthesia and 2Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 1A2, Canada
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ABSTRACT |
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Bonhomme, V., P. Fiset, P. Meuret, S. Backman, G. Plourde, T. Paus, M. C. Bushnell, and A. C. Evans. Propofol Anesthesia and Cerebral Blood Flow Changes Elicited by Vibrotactile Stimulation: A Positron Emission Tomography Study. J. Neurophysiol. 85: 1299-1308, 2001. We investigated the effects of the general anesthetic agent propofol on cerebral structures involved in the processing of vibrotactile information. Using positron emission tomography (PET) and the H215O bolus technique, we measured regional distribution of cerebral blood flow (CBF) in eight healthy human volunteers. They were scanned under five different levels of propofol anesthesia. Using a computer-controlled infusion, the following plasma levels of propofol were targeted: Level W (Waking, 0 µg/ml), Level 1 (0.5 µg/ml), Level 2 (1.5 µg/ml), Level 3 (3.5 µg/ml), and Level R (Recovery). At each level of anesthesia, two 3-min scans were acquired with vibrotactile stimulation of the right forearm either on or off. The level of consciousness was evaluated before each scan by the response of the subject to a verbal command. At Level W, all volunteers were fully awake. They reported being slightly drowsy at Level 1, they had a slurred speech and slow response at Level 2, and they were not responding at all at Level 3. The following variations in regional CBF (rCBF) were observed. During the waking state (Level W), vibrotactile stimulation induced a significant rCBF increase in the left thalamus and in several cortical regions, including the left primary somatosensory cortex and the left and right secondary somatosensory cortex. During anesthesia, propofol reduced in a dose-dependent manner rCBF in the thalamus as well as in a number of visual, parietal, and prefrontal cortical regions. At Level 1 through 3, propofol also suppressed vibration-induced increases in rCBF in the primary and secondary somatosensory cortex, whereas the thalamic rCBF response was abolished only at Level 3, when volunteers lost consciousness. We conclude that propofol interferes with the processing of vibrotactile information first at the level of the cortex before attenuating its transfer through the thalamus.
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INTRODUCTION |
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Several functional imaging
studies of the human brain have shown that physiological changes of the
level of consciousness are often associated with a change in thalamic
activity (reviewed in Paus 2000). The loss of
consciousness induced by general anesthetic agents in healthy
volunteers seems to involve brain structures identical to those
involved in the control of the sleep-waking continuum. We have
previously shown (Fiset et al. 1999
) that
propofol, a commonly used intravenous anesthetic agent, decreases in a
dose-dependent manner regional cerebral blood flow (rCBF) in several
brain regions similar to those observed to have a decrease in rCBF
during the slow-wave sleep (Hofle et al. 1997
;
Maquet et al. 1997
) including the thalamus and the brain stem.
The loss of consciousness induced by general anesthesia is accompanied
by a gradual decrease of the subject's ability to perceive his
external environment. For example, low doses of propofol suppress proprioception, finger counting, and perception of light touch in
conscious patients (Dunnet et al. 1994). It is unclear,
however, what are the brain mechanisms mediating such effects. In rats, it has been shown that propofol exerts an action on the processing of
sensory information mainly at a cortical level by blocking the
monosynaptic activation of cortical cells to thalamo-cortical input
(Angel and LeBeau 1992
). Nevertheless, propofol also
disrupts the pattern of firing of thalamic sensory relay cells; at the doses used in the above study, there was an overall increase in the
discharge probability of those cells, albeit of small amplitude (Angel and LeBeau 1992
).
In the present study, we investigated the effect of propofol-induced anesthesia on changes in brain activity induced by somatosensory stimulation. We wished to determine whether different levels of anesthesia affect differentially cortical and subcortical regions involved in the processing of vibrotactile input. Considering the effect of propofol on the processing of sensory information in rats, we hypothesized that propofol would first affect the vibration-induced CBF response in the somatosensory cortex and, presumably at a higher dose, in the thalamus.
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METHODS |
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Subjects
Eight healthy right-handed volunteers [4 males and 4 females between 18 and 29 yr of age (mean ± SD, 23.75 ± 3.92 yr)] participated in this study. All procedures were approved by the Research Ethics Committee of the Montreal Neurological Institute and Hospital and were in accordance with the Declaration of Human Rights, Helsinki 1975. Written informed consent was obtained from all subjects. The subjects were recruited through advertisement in a local newspaper and underwent a medical and physical examination before participating in the study. Blood tests were also performed to detect any blood cell or plasma ion abnormalities as well as HIV or hepatitis B. Women were tested for pregnancy no more than 1 wk before the experiment and were requested to use an appropriate contraceptive method. None of the subjects had a history of head trauma or surgery, mental illness, drug addiction, asthma, motion sickness, or previous problems during anesthesia. They had no contraindication for a magnetic resonance imaging (MRI) examination, such as vascular clips or metallic implants. All volunteers received financial compensation for inconvenience and time lost during the experiment.
Vibrotactile stimulation
Using a protocol similar to that described by Coghill et
al. (1994), vibrotactile stimuli were delivered by an electric
vibrator (Daito, Osaka, Japan) operating at a frequency of 110 Hz and
with a square stimulating surface of 1 cm2. The
stimulator was placed on the ventral surface of the subject's right
forearm alternately at one of six different locations (3 × 2 matrix with a between-site distance of 3 cm). During the 3-min scanning
period, a total of 18 vibrotactile stimuli were applied, each lasting
about 6 s and separated by an interstimulus period of 4 s.
This sequence was chosen to minimize habituation that may result from
repeated presentation of tactile stimuli at the same location.
Anesthesia
Subjects fasted for at least 8 h prior to the induction of
anesthesia and were given sodium citrate orally (0.3 M, 30 ml, BDH,
Toronto, Ontario, Canada) at their arrival in the positron emission
tomography (PET) unit to reduce gastric acidity and the risks
associated with an accidental aspiration of the gastric content.
Anesthesia was achieved with a computer-controlled intravenous infusion
of propofol to obtain constant effect-site (i.e., brain) concentrations. The software controlling the pump (Harvard Apparatus 22) was the Stanpump program developed by Steven L. Shafer and colleagues (Department of Anesthesiology, Standford University, CA;
version 12/06/95), using the pharmacokinetic parameters of Tackley et al. (1989). Propofol was infused through an
intravenous catheter placed into the right hand or forearm.
To ensure volunteers' safety, the following physiological parameters were monitored: 3-lead electrocardiogram (heart rate, HR), oscillometric invasive arterial blood pressure (left radial artery canulation), and pulse oxymetry (SpO2). Two certified anesthesiologists were present throughout the experiment, and complete resuscitation equipment was always available. Throughout the study, the subjects breathed an oxygen-enriched air spontaneously through a loosely fitting plastic face-mask. Upper airway obstruction was relieved by gentle chin support if needed. Eyes were covered by pads and ambient noise was attenuated by earplugs. The most comfortable position attainable was sought to avoid painful stimulation related to position.
Assessment of the level of consciousness and of the perception of vibrotactile stimulation
The level of consciousness was evaluated clinically throughout the study. Approximately 2 min before each scan, the subject was asked to squeeze the hand of the investigator. She/he was considered conscious if the response to verbal command was clear, and unconscious if there was no response at all. For all volunteers, the response was never ambiguous, i.e., it was either clear or absent. At the end of the experiment, subjects were asked by the experimenter to tell at which level of anesthesia they felt the vibrotactile stimulation. The perception of vibrotactile stimulation was not evaluated during the scans to avoid movements associated with speaking.
Data acquisition
PET scans were obtained using a CTI/Siemens HR+, 32-rings,
63-slices tomograph. The H215O
bolus technique was used (Raichle et al. 1983). Counts
were measured during a 3-min scan after a 10-mCi
H215O bolus injection into a
vein of the right ventral forearm. To allow for calculation of the
absolute values of CBF, arterial blood samples were acquired throughout
the scanning period using the catheter placed into the left radial artery.
The data acquisition sequence is summarized in Fig.
1. The desired target concentration of
propofol was initially set on the computer controlling the infusion
pump using the Stanpump program, which provides an estimate of the
plasma and effect-site concentration (i.e., brain concentration) of
propofol in real time (predicted plasma and effect-site
concentrations). Once the predicted effect-site concentration was equal
to the set target concentration, a 5-min equilibration period ensued to
ensure equilibration of concentrations between pharmacokinetic
compartments before clinical assessment of the level of consciousness.
Seven milliliters of blood were then drawn for the off-line measurement
of the plasma concentration of propofol (Plummer 1987).
The acquisition of the first PET scan began just after that, with or
without vibrotactile stimulation. After a 10-min resting period, the
level of consciousness was assessed again, a blood sample drawn, and
the second bolus of water injected. This scan was accompanied by
vibrotactile stimulation if the first one was not and vice versa. The
order of the scans with or without vibrotactile stimulation was
counterbalanced across subjects but remained constant throughout the
different levels of anesthesia for a given subject.
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The sequence of data acquisition described here was followed for each subject during five different levels of anesthesia. Using the computer-controlled infusion of propofol, the following plasma levels of propofol were targeted: Level W (Waking, 0 µg/ml), Level 1 (0.5 µg/ml), Level 2 (1.5 µg/ml), Level 3 (3.5 µg/ml), and Level R (Recovery, response to verbal command following the end of propofol infusion). The order of the levels of anesthesia was not randomized to limit the time spent in the tomograph and the length of anesthesia for the subject; the subjects always received an increasing concentration of propofol to avoid delays encountered by the elimination of the drug from the brain if a decreasing concentration order had been employed.
Throughout the study, systolic arterial blood pressure (SBP), diastolic arterial blood pressure (DBP), mean arterial blood pressure (MBP), and pulse oxymetry (SpO2) were recorded every 5 min for each subject. The arterial partial pressure in CO2 (PaCO2) was measured for three subjects during Levels W, 1, 2, and 3.
For each subject, high-resolution T1-weighted magnetic resonance images
(MRIs; 160 contiguous sagittal slices, 1-mm thick) were obtained from a
Philips Gyroscan ACS (1.5T) in a separate session. PET count images
were reconstructed with a 14-mm Hanning filter using the data acquired
during frame 6 to frame 14 of the 3-min scan (60 s total). The images
were normalized for differences in global CBF by means of ratio
normalization; i.e., the count at each voxel (3-dimensional image
element) was divided by the mean counts calculated across all brain
voxels (Fox et al. 1988). The images were co-registered
with individual MRIs (Woods et al. 1993
) and transformed
into a standardized stereotaxic space (Talairach and Turnoux
1988
) by means of an automated feature-matching algorithm (Collins et al. 1994
).
Statistical analysis of rCBF
Statistical analysis of rCBF was performed using normalized rCBF
of the 8 subjects, scanned 10 times each. Because of excessive movement
or technical problems, the two recovery scans for one subject, two
Level-3 scans for another subject and one Level-3 scan with
vibrotactile stimulation for a third subject were not obtained, leading
to a total number of 75 rCBF volumes (80 5 = 75). All the
calculations were carried out for each of the three-dimensional volume
elements (voxels) constituting a volume. The size of a voxel was
1.34 × 1.72 × 1.5 mm in x, y, and
z dimensions, respectively.
To assess the differences in rCBF distribution during the application
of vibration and the control condition (no vibration) at each level of
anesthesia, we calculated subtraction t-statistic maps
(i.e., vibration-ON minus vibration-OFF). For
each level of anesthesia, the data set consisted of 16 rCBF volumes (8 scans with vibrotactile stimulation and 8 scans without vibrotactile stimulation) except for Level 3 (13 volumes) and Level R (14 volumes) as explained above. A t-value was calculated for each voxel
by dividing the mean CBF difference by its standard deviation pooled across all brain voxels (Worsley et al. 1992).
We assessed the significance of the relationship between the measured
plasma concentration of propofol and the normalized rCBF
(i.e., their linear regression) by means of an analysis of covariance, ANCOVA (Sokal and Rohlf 1981), with
subjects and the effect of vibration as main effects and propofol
concentration as a covariate. The data set consisted of 45 rCBF volumes
{[8 volumes × 3 anesthesia levels (Levels 1, 2, and
3) × 2 vibration conditions (ON or OFF)]
3 missing volumes}. The parameter of interest was the slope of the
effect of the measured propofol plasma concentration versus normalized
CBF. We first removed the subject effect and the effect of vibration
and then calculated a regression t-statistic map. An
estimate of the slope and its standard deviation were obtained by
least-squares fitting of the model (ANCOVA) at each voxel. A total of
45 values of covariate was used, corresponding to the 45 volumes in the
dataset. The degrees of freedom of the standard deviation were
increased from 34 (45
8
1) by pooling the standard
deviation across all voxels, so that the distribution of the
t-statistic was normal. The resulting t-statistic
map tested whether, at a given voxel, the slope of the regression was
significantly different from zero. Using a similar approach (ANCOVA),
we assessed the interaction between vibrotactile stimulation and
propofol concentration on rCBF at a given voxel.
Cortical activity is highly variable among fully awake subjects, in the absence of any sedative drug. For that reason, including the scans recorded at Level W in the regression analysis would have introduced bias in detecting cortical regions where rCBF is correlated to propofol concentration. It is the reason why we decided to perform the regression analysis not including values recorded at Level W. As the plasma concentrations of propofol were not measured at Level R, because not reflecting brain concentrations (see comments in the legend of Fig. 5), we did not include the scans recorded at that level in the regression analysis as well.
For the subtraction, regression, and interaction t-maps, the
presence of a significant peak was tested by a method based on the
three-dimensional Gaussian random-field theory, which corrects for the
multiple comparisons involved in searching across a volume (Worsley et al. 1992). In all cases, only peaks located
in the gray matter were taken into account, assuming that any peak in the white matter is a false positive. Values equal to or exceeding a
criterion of t = 3.5 were considered significant,
yielding a false-positive rate of 0.64 in 182 resolution elements (each
of which has dimensions 14 × 14 × 14 mm) if the volume of
the gray matter is 500 cm3.
To obtain the mean relative CBF of various regions of interest, the coordinates of significant peaks observed in a t-map served as the center of a 7-mm radius volume of interest (VOI). The mean relative CBF value in that VOI was then extracted from each normalized rCBF volume. The difference in rCBF between the vibration-ON condition and the vibration-OFF condition was then calculated for each subject at each level of anesthesia and for each VOI. One-sample t-tests were performed on these data to determine whether the average difference in rCBF between the two vibration conditions was significantly different from 0. P < 0.05 was considered significant.
Calculation of the absolute CBF
The absolute CBF was calculated for the whole brain, the gray
matter, and the white matter, for each scan of each subject. We used
the two-compartment weighted integration method of Ohta and colleagues
(Ohta et al. 1996). Cerebral perfusion maps (K1 maps)
were generated for each 3-min scan of each subject using the sum of the
native PET images across all frames. Mean whole-brain CBF values were
then obtained by averaging the K1 maps.
The mean CBF values in the gray and the white matter were obtained by masking the K1 maps with standard probabilistic maps of gray or white matter that were co-registered with each K1 map. A probability of 0.6 was chosen as a cutoff point for a voxel to be of gray or of white matter, respectively.
The significance of the differences in absolute CBF was assessed using a three-way ANOVA for related samples, the first factor being anesthesia level (Level W, Level 1, Level 2, Level 3, and Level R), the second factor being the brain volume (whole brain, gray matter, or white matter), and the third one being the vibration condition (OFF or ON). Tukey's HSD tests were used for post hoc comparisons, and P < 0.05 was considered significant. Three subjects were displaying missing data and were excluded from this analysis.
Statistical analysis of the vital signs
We analyzed the variability of HR, SBP, DBP, MBP, and SpO2 across conditions using a one-factor within-subjects ANOVA and Tukey's HSD for post hoc comparisons. A Bonferoni corrected P < 0.01 was considered significant.
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RESULTS |
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Propofol concentrations
The plasma propofol concentrations were as follows (mean ± SD, 7 subjects): 0.55 ± 0.14 for Level 1, 1.52 ± 0.25 for Level 2, and 3.45 ± 0.61 for Level 3. For technical reasons, plasma concentrations of propofol were not available for one subject at all levels and were not measured for all subjects at Level R (see comments in the legend of Fig. 5). We used the mean measured plasma concentration of propofol to replace the missing values at Levels 1, 2, and 3 for further analysis. The mean and median absolute errors on propofol plasma concentrations in the seven remaining subjects were 3.4 and 1.0% of the values predicted by the Stanpump program, respectively. The correlation between the predicted propofol plasma concentration and the measured propofol plasma concentration was excellent (r = 0.97).
Evaluation of the level of consciousness
All volunteers were conscious but mildly sedated at Level 1. They responded clearly to verbal commands and reported being slightly drowsy. At Level 2, all subjects were moderately sedated, having a slurred speech and responding slower but still clearly to verbal commands. At Level 3, all subjects were unconscious, i.e., they were not responding to verbal commands at all. At the end of the experiment, all subjects remembered clearly having felt the vibrotactile stimulation during Levels W, 1, and R, but not during Levels 2 and 3.
Vital signs
The means ± SD of the vital signs for the eight volunteers across the levels of anesthesia are shown in Fig. 2. The vibrotactile stimulation did not affect the values observed at each level of anesthesia. There was a significant decrease in SBP, MBP, and DBP at Level 3 compared with all other levels (P < 0.01). There was no significant change in HR or SpO2 across levels, although the tendency was toward an increase from Level W to Level 3 for HR. The PaCO2 (in mmHg) measured in three subjects during Levels W, 1, 2, and 3 increased from 42.7 ± 3.1 at Level W, 43.9 ± 5.84 at Level 1, and 46.33 ± 4.33 at Level 2 to 51.1 ± 8.84 at Level 3 (means ± SD; Fig. 3). Significant upper airway obstruction in three subjects during Level 3 necessitated chin holding to facilitate spontaneous respiration.
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CBF
The mean absolute whole-brain, gray-matter and white-matter CBF at each level of anesthesia is summarized in Fig. 3 (n = 5). A three-way ANOVA for related samples performed on these data revealed a significant main effect of brain volume (F2,8 = 145.35, P < 0.0001) and anesthesia level (F4,16 = 4.5, P < 0.05). Post hoc pair-wise comparisons revealed that CBF was significantly higher in the gray matter than in the whole brain and in the white matter (P < 0.01). CBF was also higher in the whole brain than in the white matter (P < 0.05). It increased significantly from Level 2 to Level 3 (P < 0.05) and decreased significantly from Level 3 to Level R (P < 0.05). Interaction between brain volume and anesthesia level was not significant (F8,32 = 1.18, P = 0.34).
rCBF
MAIN EFFECT OF PROPOFOL. A regression t-statistic map is presented in Fig. 4A, and the significant peaks determined from this analysis are shown in Table 1. A negative correlation between the measured plasma concentration of propofol and rCBF was observed in the thalamus, the left and right precuneus, the left and right posterior cingulate gyrus, the left and right angular gyrus, the left superior parietal lobule, and several regions in the prefrontal cortex. Positive correlation was found in the cerebellar vermis, the left cerebellar lobe, the left postcentral gyrus, and the left gyrus rectus.
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MAIN EFFECT OF VIBROTACTILE STIMULATION. Representative slices of subtraction t-statistic maps (vibration-ON minus vibration-OFF) at Levels W, 1, 2, and 3 are shown in Fig. 4B. As summarized in Table 2, vibrotactile stimulation of the right forearm during waking (Level W) induced an increase in relative CBF in several regions, including the left thalamus, the left primary somatosensory cortex (S1), the left and the right secondary somatosensory cortex (S2), and the left superior frontal gyrus (midline). Vibrotactile stimulation led to rCBF decreases in the left and the right cuneus, the left and the right lingual gyrus, the left fusiform gyrus, and the left middle occipital gyrus.
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INTERACTION BETWEEN THE EFFECT OF PROPOFOL AND THE EFFECT OF VIBRATION. We did not find any significant peak in the interaction t-statistic map. However, as illustrated in Fig. 4B, the vibration-induced CBF response in the primary somatosensory cortex and in the thalamus differed across the different levels of anesthesia. At Level 1, there was no significant positive peak in the subtraction map, although we observed t-values of 2.86 and 3.22 in the thalamus and left S2, respectively. At Level 2, we found a significant positive peak in the thalamus (t = 5.47). At Level 3, no significant peaks were observed either in the somatosensory cortex or in the thalamus. Furthermore, as illustrated in Fig. 5, the analysis of rCBF in selected VOIs led to the same conclusion. Figure 5 illustrates the difference in rCBF between the vibration-ON condition and the vibration-OFF condition at each level of anesthesia in a 7-mm radius VOI centered at the coordinates of the thalamic, S1, and S2 peaks obtained in the subtraction map at a given anesthesia level. If no peak was observed for a given VOI at a given anesthesia level, the coordinates of the peak observed at Level W were used. Statistical analysis of those data (1-sample t-tests) is reported in the legend of Fig. 5. It revealed that, during propofol administration, at Level 2 in the thalamus and at Level 1 in left S2, rCBF remained significantly higher when vibration was applied than when it was not. This is not true in left S1 and right S2.
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DISCUSSION |
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The main findings of the present study can be summarized as follows. First, propofol tended to reduce the absolute global CBF as its concentration increased, except for the deepest level of anesthesia, where we observed an increase in CBF. Second, propofol reduced in a dose-dependent manner normalized rCBF in specific brain regions including the thalamus and several cortical regions. Third, propofol affected the vibration-induced increases in rCBF differentially in cortical and subcortical regions.
Rationale for choosing propofol
Propofol is a commonly used general anesthetic agent with
relatively pure hypnotic properties (White 1997). The
development of computer-driven administration systems, such as the one
used in the present study, allows targeting of precise brain
concentrations of the anesthetic agent (Shafer 1993
).
Several animal studies have investigated the central effects of
propofol and suggested that its anesthetic effects may result at least
partially from an inhibition of thalamocortical transfer of information
(for a review, see Yaksh et al. 1998
). Nevertheless,
little is known about its effect on the functioning human brain. We
recently observed a dose-dependent reduction in thalamic activity by
propofol, suggesting that propofol might reduce thalamo-cortical
information transfer in humans (Fiset et al. 1999
).
Further studies are needed to determine whether other general
anesthetic agents have similar effects on thalamocortical sensory
transfer as does propofol.
Effect of propofol on the absolute CBF
Propofol is known to reduce the cerebral metabolic rate of
O2 (CMRO2) and CBF in
animals (Enlund et al. 1997) as well as in humans
(Newman et al. 1995
). It has been suggested that
anesthetic agents can interfere with normal metabolism-flow coupling in
the brain (Jezzard et al. 1997
), but several human and
animal studies have provided strong evidence against this notion for
propofol (Enlund et al. 1997
; Newman et al.
1995
).
In our previous study (Fiset et al. 1999), the infusion
of propofol targeted to reach a plasma concentration of 3 µg/ml
reduced the mean whole-brain CBF by 22%. In the present study, we
observed an initial (nonsignificant) decrease of the mean whole-brain
CBF from the awake baseline state (Level W) to the moderately sedated state (Level 2). Surprisingly, as propofol concentration further increased and subjects progressively lost consciousness (Level 3), this
decrease was followed by the return of CBF values to values close to
baseline or even higher. At Level 3, all subjects were unresponsive to
verbal commands, three of them needed chin holding to support
ventilation, and the PaCO2 measured in three volunteers substantially increased by approximately 20% at Level 3 compared with Level W (Fig. 3). This increase in
PaCO2 is related to the central depression of
ventilation by propofol and to the obstruction of the upper airway
associated with the reduced muscle tone (pharynx, tongue, jaw) observed
during propofol anesthesia (Fragen and Avram 1992
). An
increase in PaCO2 is known to cause cerebral
vasodilatation, leading to an increase in CBF and cerebral blood volume
(Brust 1991
). Propofol does not affect cerebrovascular reactivity to CO2 (Stephan et al.
1987
), and it preserves the autoregulatory response to
variations in arterial blood pressure (Strebel et al.
1995
). It is therefore likely that the observed evolution of
the mean whole brain CBF in our study results from opposite effects of
propofol and PaCO2, the effect of propofol being
antagonized by the effect of CO2 at Level 3. Although the arterial blood pressure was significantly lower at Level 3 than at the other levels, it probably did not affect CBF, as the
autoregulatory response to variations in arterial blood pressure was
probably preserved. In our previous study (Fiset et al.
1999
), mean end-tidal PCO2 increased only
by 10%, probably because the highest concentration of propofol reached
(3 µg/ml) was lower than the concentration reached in the present
study (3.5 µg/ml).
Effects of propofol on rCBF
The infusion of propofol reduced rCBF in brain regions identical
to those described in our previous study (Fiset et al.
1999) except for several additional peaks in the frontal cortex
observed in the present study. This could be related to the fact that
the propofol concentrations used were lower in that study than in the
present one. We therefore confirm our previous findings and provide
further evidence in support of the region-specific, rather than global,
mode of action for this general anesthetic.
The brain regions where propofol concentration and rCBF were
positively correlated are the cerebellum, the left postcentral gyrus,
and the orbitofrontal cortex. In our previous study (Fiset et
al. 1999), we observed a similar trend in the cerebellum, the medial frontal gyrus, and the left temporal lobe. Discussion about the
functional significance of the positive correlation between rCBF and
propofol concentration can be found in Fiset et al.'s paper.
Although we were not able to randomize or counterbalance the order in
which increasing doses of propofol were delivered to each subject, the
distribution of brain regions where rCBF is significantly correlated
with the measured plasma concentration of propofol is unlike that
observed in PET studies examining nonspecific effects of time on rCBF.
For example, Athwal and colleagues demonstrated a nonspecific rCBF
increase with time in large confluent regions of both frontal lobes and
a nonspecific decrease with time in posterior regions of the left and
right temporal lobe (Athwal et al. 1998).
Effects of propofol on vibration-induced rCBF changes
During waking, we observed a robust vibration-induced increase in
rCBF in the left (contralateral) primary somatosensory cortex, the left
and the right secondary somatosensory cortex, and in the thalamus, a
finding consistent with previous studies (Coghill et al.
1994).
In the voxel-based analysis, we did not find a significant interaction between the effect of anesthesia level and the effect of vibration. This lack of significant interaction can be related to slight changes of the coordinates of peak vibration-related activity from one anesthesia level to the other. For this reason, we performed the VOI-based analysis, using the coordinates of the thalamic, the primary, and the secondary somatosensory cortex peaks observed at each level of anesthesia in the subtraction maps. This analysis confirmed that vibration was still able to induce a significant increase in left S2 rCBF at Level 1 and in thalamic rCBF at Level 2. Based on both the voxel-based subtraction analysis and the VOI-based analysis, the vibration-induced increase in rCBF disappears only at Level 3 in the thalamus. It is still present at Level 1 (t = 2.86), highly significant at Level 2 (t = 5.47), and absent at Level 3. On the contrary, the vibration-induced increase in rCBF of the left S1 observed at Level W is not present at Levels 1, 2, or 3. Thus the blood-flow response observed at Level W was attenuated first in the primary somatosensory cortex and then in the thalamus.
In rats, propofol alters the transmission of sensory information
primarily by acting on cortical cells and by blocking the monosynaptic
activation of cortical cells by thalamo-cortical input. It also
disrupts the pattern of firing of thalamic sensory relay cells. Unlike
other general anesthetic agents that affect the ascending transmission
of sensory information both by activating corticothalamic inhibitory
mechanisms and by reducing the thalamo-cortical transfer of information
through the thalamic relay nuclei, propofol increases the discharge
probability of the thalamic relay cells, although the amplitude of
discharge is reduced (Angel and LeBeau 1992). The fact
that the cortical activation observed in our study disappears at lower
doses than the thalamic activation is consistent with these
observations and those of Ergenzinger et al., who have demonstrated
that chronic and acute suppression of neuronal activity in the primary
sensory cortex of primates increases the receptive field size in the
ventroposterior thalamus (Ergenzinger et al. 1998
).
As long as the volunteers remained conscious, there was still a thalamic activation by vibrotactile stimulation. This activation disappeared only at higher concentrations of propofol, when subjects were unconscious. Subjects clearly perceived vibrotactile stimulation at Levels W and 1, but it was less evident at Level 2. At least, they did not remember having perceived it at that level. As cortical inhibition by propofol alters sensory perception without altering consciousness, it seems that consciousness is lost only when the concentration of propofol is high enough to reduce sufficiently the thalamic activation induced by external stimulation.
Vibration-induced deactivations observed at Level W disappeared at the
other levels except for poorly significant peaks in the medial frontal
gyrus at Levels 1 and 2 and in the right cuneus at Level 2. No
significant deactivation was observed at Level 3. As hypothesized by
Coghill et al. (1994), decreased rCBF may indicate areas
that exhibit increased activation during the control condition or may
indicate a real reduction in activity. A reduction in rCBF is unlikely
to be related to a local inhibitory process, since the release of
inhibitory neurotransmitters is considered an energy-demanding process.
A decrease in rCBF would more likely be related to a diminished input
to the region that results from active inhibition occurring at a
preceding level of processing. There could also be a passive shunting
of blood to nearby activated areas. Deactivation in regions of the
occipital lobe is a common feature of changes in cortical activity
associated with the processing of other sensory modalities, including
skin and muscle pain (Svensson et al. 1997
). The
occipital deactivations observed in the present study disappeared at
high propofol concentrations. The physiological significance of those
observations remains unclear.
Conclusions
In conclusion, the present study confirms our previous findings that propofol differentially decreases rCBF in specific brain regions and that those concentration-dependent decreases are associated with changes in the level of consciousness. The present study also shows that propofol differentially affects the brain regions involved in the processing of somatosensory information. At low concentrations, it suppresses vibration-induced blood-flow response in the primary somatosensory cortex. At intermediate concentrations, it suppresses all cortical activation induced by vibration and alters the perception of stimuli. The loss of consciousness occurs only at higher propofol concentrations and coincides with a suppression of vibration-induced blood-flow response in the thalamus. Those differential effects may be critical mechanisms mediating the effect of anesthetic drugs on the patient's conscious perception of the external environment and on consciousness. They may reflect sequential effects of these agents on the complex reciprocal thalamocortical system sustaining the concerned higher brain functions.
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ACKNOWLEDGMENTS |
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We thank the following persons for help in data analysis, technical support during PET data acquisition, and volunteer management before, during, and after the completion of the experiments: M. Vafaee, S. Milot, P. Neelin, G. Sauchuk, R. Fukasawa, M. Shingler, L. Ulliat, and the main operating room and recovery room staff of the Royal Victoria Hospital.
This study was supported by the Medical Research Council (Canada), the Canadian Anaesthetists' Society (Abbott Laboratory Research Award), le Fonds de la Recherche en Santé du Québec (G. Plourde), le Centre Hospitalier Universitaire de Liège, Belgium, and the Government of Quebec (V. Bonhomme), l'Association des Anesthésistes du Québec, and the Associated Anesthetists of the Royal Victoria Hospital.
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FOOTNOTES |
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Present address and address for reprint requests: P. Fiset, Royal Victoria Hospital, Dept. of Anesthesia, 687 Pine Ave. West, Suite S5.05, Montreal, Quebec H3A 1A1, Canada (E-mail: mdft{at}musica.mcgill.ca).
Received 22 March 2000; accepted in final form 17 November 2000.
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REFERENCES |
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