A Imaging Researches Of The Functional Sites Of Intravenous Anesthetics And Its Neurotransmitter Metabolism In The CNS Of Human

Propofol and midazolam have been extensively used clinically as a sedative and intravenous anesthetics. Although the therapeutic applications of them are diverse, its mechanisms of action and pricise binding sites remain largely unclear. In the present papers, more work in ex vivo provided evidence that anesthetic interactions with specific receptors or other molecular targets. While such studies are important, they are difficult to explain the actual situation in vivo, ultimately general anesthesia is a biological effect in vivo induced by anesthetics . If the related researches are carried in human body or in vivo, it will provide the truth and reliable datas for interpreting general anesthesia mechanisms. In addition, it is generally accepted that intravenous anesthetics act primarily by effected neurotransmitter, then researching the change of neurotransmitter is an aid to know the characters of anesthetics action. In the present study, we will apply varied brain imaging techniques to investigate the key targets for intravenous anesthetics action in the CNS and the changes of neurotransmitters in the correlated regions from volunteer, clarity the mechanisms ofintravenous anesthetics action in the CNS.Part I Imaging study in the effect of intravenous anesthetics on cerebral metabolism with positron emission tomography in healthy volunteersObjective: Using the positron emission tomography technology, to examine the changes in regional cerebral glucose metabolism produced by propofol or midazolam and investigate the sensitive sites effected by intravenous anesthetics. Methods: Volunteers in propofol groups underwent PET scans for three times. The first scan assessed awake-baseline metabolism. The second scan assessed metabolism during sedation of propofol (TCI 1.5ug/ml). The third scan assessed metabolism at loss of consciousness of propofol (TCI 3.0ug/ml). Volunteers in midazolam groups underwent PET scans for three times. One scan assessed awake-baseline metabolism. The second scan assessed metabolism during sedation of midazolam (TCI 50ng/ml). The third scan assessed metabolism at loss of consciousness of midazolam (TCI 80ng/ml). Once stableness under the target level, The participants were given 5 mCi FDG intravenously over a period of 1 min. After this uptake period, the anesthetic was discontinued and the participants were allowed to emerge from anesthesia, then were taken to the PET scan. Results: (1) propofol anesthesia: Propofol anesthesia reduced whole-brain glucose metabolism 18.0 % at sedation, Compared with awake, rCMRGlu decreased throughout the brain, mainly in frontal lobe, temporal lobe and occipital lobe. Propofol anesthesia reduced whole-brain glucose metabolism 34.1% at loss of consciousness, Compared with awake, CMRGlu decreasedthroughout the brain,mainly in thalamus, cerebral cortex, hippocampus, cerebellum and so on. ?Midazolam anesthesia: Midazolam anesthesia reduced whole-brain glucose metabolism 8.7% at sedation, Compared with awake, rCMRGlu decreased throughout the brain, mainly in frontal lobe, temporal lobe and occipital lobe(P<0.05). Midazolam anesthesia reduced whole-brain glucose metabolism 12.7% at loss of consciousness, Compared with awake, rCMRGlu decreased in most cerebral regions, especially thalamus, frontal lobe, cingulated gyms (P<0.05). Conclusions: Whole brain and most regional metabolism decrease significantly during propofol or midazolam anesthesia. Low doses of anesthetics seemed to affect cortical areas preferentially, and higher doses of anesthetics did not only affect cortical but also subcortical brain structure, in particular, thalamus, hippocampus and cingulated gyms, these regions may be the primary targets in anesthetics action, but it may be exits partially difference in key structures between two anesthetics.Part II Imaging study in the effect of intravenous anesthetics on cerebral blood flow with SPECT in healthy volunteersObjective: Using the SPECT technology, to examine the changes in regional cerebral blood flow produced by propofol or midazolam and investigate specific brain regions that are important for anesthesia and by inference, for the generation of sedation or unconsciousness. Methods: Anesthesia procedures and anesthetics dosage were same as part one. Volunteers in propofol groups or midazolam seperately underwent SPECT scans for three times. One scan assessed awake-baseline rCBF. The second scan assessed cerebral blood flow during sedation. The third scan assessed cerebral blood flow at loss of consciousness. Once stableness under the target level, The participants were given 0.6mCi "Tcm-ECD intravenously over a period of 1 min. After this uptake period, the anesthetic was discontinued and the participants were allowed to emerge from anesthesia, then were taken to the SPECT scan. Results: ? propofol anesthesia: Propofol anesthesia reduced whole-brain blood flow 14.8% at sedation, this effect was particularly pronounced in the cerebral cortex(P<0.05). Propofol anesthesia reduced whole-brain blood flow 24.3 % at loss of consciousness, Compared with awake, rCBF decreased throughout the brain, mainly in thalamus, cerebral cortex, hippocampus, cerebellum and so on. ?Midazolam anesthesia: Midazolam anesthesia reduced whole-brain blood flow 4.7% at sedation, Compared with awake, rCBF decreased mainly in frontal lobe and parietal lobe(P<0.05). Midazolam anesthesia reduced whole-brain blood flow 10.9% at loss of consciousness, Compared with awake, rCBF decreased in most cerebral regions, especially thalamus, frontal lobe, cingulated gyrus (P<0.05). Conclusions: Propofol and midazolam induced a genera-llized decrease in global CBF. Low doses of anesthetics seemed to affect CBF distribution in cortical areas preferentially, and higher doses of anesthetics did not only affect cortical but also subcortical brain structure, in particular, thalamus, hippocampus and cingulated gyrus, these regions may be the primary targets in anesthetics action. The effect on cerebral blood flow by intravenous anesthetics is coupled to regional energy metabolism.Part HI Imaging study in the effect of intravenousanesthetics on cerebral function with functional magnetic resonance imaging in healthy volunteersObjective: Using the BOLD-fMRI technology, to examine the changes of BOLD signal in distinct cerebral regions produced by propofol or midazolam and investigate specific brain regions that are important for anesthesia. Methods: Anesthetics were used for stimulation, stimulus procedure included awake > sedation unconsciousness^ analepsia process. Scan lasted 50 Dy for propofol, and 60 Dy for midazolam. Anesthetics were inject from the tenth Dy. Propofol was delivered at rate of 1.5 mg/kg using a constant speed infusion pump, midazolam was taken at rate of O.lmg/kg. Functional magnetic resonance images were acquired during the entire experimental session. A dynamic single-shot EPI sequence was used to perform functional MR imaging on a 1.5T Philips gyroscan MR system. Regional activation was measured in the sagital imaging planes and then analyzed by functool software in BOLD function package of workstation. Results: (D propofol anesthesia: The decreased in signal intensity were observed in hypothalamus(r=0.75, 20.2%), frontal lobe(r=0.71, 37.5%), temporal lobe(r=0.72, 33.8%). The changes of signal intensity were at equal pace, the decreased of signal intensity from higher to lower was frontal lobe > temporal lobe > hypothalamus, but there was not a significant deviation. Significant decrease was visible in thalamus(r=0.60, 3.9%), compared to regions in frontal lobe, temporal lobe, hypothalamus, there was remarkable difference at the changes of signal intensity in thalamus. (2) Midazolam anesthesia: The decreased in signal intensity were observed in hypothalamus(r=0.78, 18.2%), frontal lobe(r=0.76, 20.5%),temporal lobe(r=0.82, 17.8%), parietal lobe(r=0.74, 28.8%), their changes of signal intensity were synchronization, the decreased of signal intensity from higher to lower was parietal lobe > frontal lobe > hypothalamus > temporal lobe, but there was not significant difference. Remarkable decreased was seen in thalamus(r=0.65, 4.5%), hippo-campus(r=0.58, 3.4%), basal ganglia(r=0.55, 4.1%), their changes of signal intensity were synchronization, but delayed to regions of frontal lobe and so on, there was not significant difference in above-mentioned regions. Compared with regions in frontal lobe and so on, there was remarkable difference at the changes of signal intensity in thalamus, hippocampus, basal ganglia. Conclusions: Propofol anesthesia firstly affected hypothalamus, frontal lobe, temporal lobe, then affected thalamus region, these regions may be the key targets for propofol action. Midazolam anesthesia firstly suppressed regions in hypothalamus, frontal lobe, temporal lobe and parietal lobe, whereafter suppressed regions in hippocampus, basal ganglia and thalamus, these regions may be the key targets for midazolam action.Part IV Imaging study in the effect of intravenous anesthetics on neurotransmitter metabolism with 1H-magnetic resonance spectrography in healthy volunteersObjective: To investigate the changes of neurotransmitter metabolism in different cerebral regions produced by propofol of midazolam in volunteers using the proton magnetic resonance spectroscopy technology and clarity mechanism of intravenous anesthetics action. Methods: Anesthetic procedures and dosage were same as part one. Each of volunteers underwent three MRS scan, one scan assessedawake baseline the levels of neurotransmitter metabolism, The other two scan separately assessed sedative level and unconscious level of neurotransmitter metabolism. Volume of interest included sensory cortex, motor cortex, thalamus, hippocampus and basal ganglia. The metabolites in the spectra included: NAA> Glu> GABA> ChoandCr. Results: (Dpropofol anesthesia: Glu in sensory cortex > motor cortex and thalamus were significant decreased in sedation(P<0.05). Cho in thalamus were significant decreased in sedation(P<0.05). Compared with awake group, NAA content of thalamus and hippocampus was significantly decreased in unconsciousness(P<0.05); the decrease of Glu was obvious in thalamus % hippocampus and basal ganglia during propofol anesthesiaCPO.05); GAB A in sensory cortex % motor cortex n thalamus n hippocampus and basal ganglia increased significantly in unconsciousness; But Cho content in the five regions decreased significantly; Cr content in the five areas did not change significantly. ?Midazolam anesthesia: Compared with awake group, significant decreased of Glu were observed in sensory cortex ^ motor cortex during sedation(P<0.05), and significant decreased of Cho were observed in thalamus(P<0.05), but NAA> GABA^ Cr in above-mentioned five regions had no significant changed. Compared with awake group, NAA in thalamus decreased in unconsciousness, Cho content in motor cortex and thalamus regions decreased significantly; GABA in five regions increased significantly in unconsciousness (PO.05); But Glu content in the five regions decreased significantly (PO.05). Conclusions: Intravenous anesthetics action closely relates to neurotransmitters metabolism in sensory cortex, motor cortex, thalamus, hippocampus and basal ganglia, among the total, it is one of important mechanisms that anesthetics depress the effect of Glu...