Consciousness and Anesthesia Takashi Mashimo (Graduate School of Medicine) 眞下 節（医学系研究科麻酔･集中治療医学教室） ･General Anesthesia ・Anesthesia and EEG ・Mechanism of Anesthesia -GABAA Receptor- Global COE Cognitive Neuroscience Robotics General Anesthesia Operation without Anesthesia First Anesthesia with Ether by Dr. Morton in 1846 A Patient under General Anesthesia Purpose of General Anesthesia • Amnesia and Unconsciousness • Immobility with Surgical Stimuli • Suppression of Stress Responses to Surgical Stimuli Three Requisites for General Anesthesia • Sedative, Hypnotic (Anesthetic) • Analgesic (Opioid) • Muscle Relaxant Inhalational Anesthetics Anesthesia Machine Intravenous Anesthetics Continuous Infusion of Propofol and Remifentanyl Components of the Anesthetized State • General anesthesia consists of several components. • Some of the discrete brain regions and neural circuits are involved in specific components of the anesthetized state. • General anesthetics interact with subpopulations of nervous system cells to create each of the separate properties of anesthesia Main Components of General Anesthesia • • • • • • Sedation（鎮静、思考力低下） Amnesia（記憶消失） Unconsciousness, Hypnosis （無意識） Analgesia（無痛） Immobility（不動化） Adrenergic Suppression（交感神経抑制） Sites in the CNS that are thought to be involved in the anesthetic components; sedative, hypnotic and immobilizing actions of propofol Correlation between propofol level and anesthetic depth Rudolph & Antkowiak: Nature Reviews Neuroscience 5: 709, 2004 Dose-response Curves of Main Components of General Anesthesia ED50s of Dose-response Curves of Anesthetic Components: Amnesia＜Unconsciousness＜Immobility＜Adrenergic Suppression How do Anesthetics Produce the Broad Effects throughout the Brain？ • Individual aspects of the anesthetized state are attributable to different sets of nerve cells, which are themselves distinguished by specific surface proteins (receptors) that interact with anesthetics. • New compounds designed to target just those proteins, and hence the desirable effects of anesthetics –as well as sedatives, sleep aids and memory drugs. Anesthesia and EEG Arousal (Consciousness) and Anesthesia (Unconsciousness) Unconsciousness (Hypnosis) • Mechanism of arousal (consciousness) is complex. • Centers of arousal are thought to be frontal cortex, thalamus and midbrain reticular formation. • It is difficult to pinpoint a single anatomical source of unconsciousness during anesthesia. • Unconsciousness is simply the result of cognitive unbinding: a severing of communication between the many brain regions that cooperate in higher cognition processing. GABAA Receptor and EEG 10Hz spindle wave GABAA Receptor Activation of GABAA receptor with general anesthetics Increase in amplitude of 10Hz spindle wave Electroencepharogram (EEG) Dendrite of Cone Cell － －－ － －－ Cerebral Cortex － － ＋＋＋ ＋ ＋ Cone Cell ＋ ① Thalamus EEG is thought to originate in the cone cells of cerebral cortex. Stages of Sleep and EEG • Stage 2: 10Hz spindle waves • Stage 3: 2Hz slow waves (20~50%) • Stage 4: 2Hz slow waves (over 50%) Changes in EEG during Anesthesia Awake/light anesthesia: low amplitude rapid wave Low amplitude 1 sec 10Hz Moderate anesthesia: high amplitude slow wave High amplitude 1 sec 5Hz BIS (EEG) Electrode during Anesthesia BIS value 100 Sevoflurane Anesthesia and EEG Awake 80 +50 Light anesthesia 低振幅速波 0 -50 +50 60 Moderate anesthesia 高振幅徐波 （α wave） 0 高振幅徐波 （δwave） 20 0 -50 Deep anesthesia BIS = 60 4 (sec) BIS = 40 4 (sec) BIS=15 Burst & suppression +50 0 4 (sec) -50 +50 40 BIS = 80 Too deep anesthesia Flat EEG 0 -50 BIS = 0 4 (sec) Power Spectrum of EEG 2% sevoflurane anesthesia +50 0 -50 4 (sec) ① ② ② 2Hz Power spectrum of EEG ① 10Hz EEG Power Spectra during Sevoflurane Anesthesia Sevoflurane 1.0% BIS 61 Sevoflurane 1.5% BIS 53 Sevoflurane 2.0% BIS 46 2Hz 10Hz EEG Power Spectra during Sevoflurane Anesthesia in Infants and Adults Infant Adult 1.0% 1.5% 2.0% 2.5% Concentration of sevoflurane (%) 3.0% Sevoflurane Concentrations in Which an Amplitude of the EEG’s 10Hz wave Reaches the Highest P<0.05 2.3±0.3% 1.8±0.4% Sevoflurane (%) Infant Adult Mechanism of General Anesthesia The effect of anesthesia is analogous to pulling out plugs at the switchboard in the brain • Unconsciousness is simply the result of cognitive unbinding: a severing of communication between the many brain regions that cooperate in higher cognition processing. • If one imagines groups of neurons as forming lines in a vast telephone network, the effect of general anesthesia is analogous to pulling out plugs at the switchboard. Anesthetics interacts with multiple varieties of specific proteins, known as receptors, on the surface of neurons Receptors and Anesthetics • Anesthetics interacts with multiple varieties of specific proteins, known as receptors, on the surface of neuron cells. • Families of receptors contain different versions which tend to predominate in different areas of the CNS. The presence of particular receptor subtypes on only certain subpopulations of neurons will determine which cells are influenced by an anesthetic. • Receptor variants are the targets of current anesthetic drugs, understanding how the drugs interact with the receptors to change the cell’s function and how those cellular changes produce the components of anesthesia. GABA and GABAA Receptor • GABA is an inhibitory neurotransmitter, which has the ability to block neuronal communication • It helps to maintain overall balance in the CNS by dampening neuron’ ability to respond to excitatory messages from other cells. • GABAA receptor is thought to play a central part in the actions of anesthetics Orser BA, Sci Am, June:32-9,2007 GABAA receptor plays a central part in the actions of anesthetics • Anesthetics increases the function of GABAA receptors by interacting at discrete binding cavities or attaching to specific amino acids in the receptors themselves. • Anesthetics prolong the chloride ion channel opening, which causes hyperpolarization of the cell membrane. • It extends the inhibitory effects of GABA molecules bound to the receptor. Anesthetics and GABA:Changing Charge Orser BA, Sci Am, June:32-9,2007 Anesthetics bind the GABAA receptor and prolonging the channel opening, which causes hyperpolarization of the cell membrane GABAA Receptor • GABAA receptor is a protein complex composed of five subunit parts, which can be mixed and matched in various combinations. • At least 19 different GABAA receptor subunits exists in mammals, and most of those have variant subtypes. • Most GABAA receptors are composed of 2 alpha subunits, 2 betas and 1 gamma. GABAA Receptor’s Subunit Composition The GABAA receptor’s subunit composition dramatically alters its pharmacological properties: just one subunit difference within a GABAA receptor’s structure can determine whether and how it will respond to a particular anesthetic drug. Anesthetics is Jamming Nervous Transmission • Anesthetics dampen neuronal communication, in part, by enhancing the effects of neurotransmitter GABA, a signaling molecule that inhibits nerve cells from firing. • Current research is focused on how the anesthetics interact with cellular GABAA receptors to block neural activity. 神経受容体発現と電気生理学的測定 cDNA ﾌﾟﾗｽﾐﾄﾞに組み込み ２電極電位固定 法 cDNA pBluescript 大腸菌内で大 量に増殖 プラスミドを収穫 し，制限酵素で直 線化 24-48時間培養 Xenopus oocyte cDNA ﾌﾟﾛﾓｰﾀｰ部 位より翻訳 ｱﾌﾘｶﾂﾒｶﾞｴ ﾙ卵へ注入 mRNA Amino-acid Point Mutations in β2(N265S) Mice and β3(N265M) Mice Unconsciousness Rudolph & Antkowiak: Nature Reviews Neuroscience 5: 709, 2004より引用 Behavioural Responses to Intravenous Anesthetics in β3(N265M) Mice and β2(N265S) Mice Rudolph & Antkowiak: Nature Reviews Neuroscience 5: 709, 2004より引用 Effects of Volatile Anesthetics on Ligand-gated Ion Channels サブタイプ Halothane Isoflurane Sevoflurane Potentiation Potentiation Inhibition α4 β2 Inhibition Inhibition Inhibition α7 Inhibition No effect αβγδ Little inhibition Little inhibition Little inhibition GABAA受容 体 Potentiation Potentiation Potentiation NMDA受容 体 Inhibition Inhibition Inhibition 5-HT3受容体 nACh受容体 5-HT3A 神経 性 骨格 筋 Machu et al. J Pharmacol Exp Ther 1994 Jenkins et al. Br J Pharmacol 1996 Violet JM et al. Anesthesiology 1997 Flood P et al. Anesthesiology 1997 Jenkins A et al. Anesthesiology 1999 Hollmann MW et al. Anesth Analg 2001 Effects of Gaseous Anesthetics on Ligand-gated Ion Channels サブタイプ 5-HT3受容体 5-HT3A Xe N2O Inhibition Inhibition 神経 nACh受容体 性 α 4β 2 Inhibition Inhibition α7 Inhibition Inhibition 骨格 筋 αβγδ GABAA受容 体 No effect Potentiation No effect Potentiation NMDA受容 体 Inhibition Inhibition Yamakura et al. Anesthesiology 2000 Suzuki et al. Anesth Analg 2003
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