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-

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）

Rudolph & Antkowiak: Nature Reviews Neuroscience 5: 709, 2004

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

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

Activation of GABAA receptor with general anestheticsGABAA Receptor

Increase in amplitude of 10Hz spindle wave

Electroencepharogram (EEG)

EEG is thought to originate in the cone cells of cerebral cortex.

①

Cerebral Cortex

Thalamus

Dendrite of Cone Cell

Cone Cell

＋＋

＋＋

－－

－ －－ －

－

－

＋＋

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

1 sec

Low amplitude

Awake/light anesthesia: low amplitude rapid wave

5Hz

1 sec

High amplitude

Moderate anesthesia: high amplitude slow wave10Hz

BIS (EEG) Electrode during Anesthesia

BIS = 80

BIS = 60

BIS = 40

低振幅速波

高振幅徐波（ α wave ）

Burst & suppression

Flat EEG

BIS value100

0

80

60

40

20

Awake

Moderate anesthesia

Deep anesthesia

Too deep anesthesiaBIS = 0

Sevoflurane Anesthesia and EEG

+50

0

- 50

4(sec)

+50

0

- 50

4(sec)

+50

0

- 50

4(sec)

高振幅徐波　（ δwave ） BIS=15

+50

0

- 50

4(sec)

Light anesthesia

+50

0

- 50

4(sec)

Power Spectrum of EEG

① ②

① 10Hz

② 2Hz

2% sevoflurane anesthesia

Power spectrum of EEG

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% 3.0%

Concentration of sevoflurane (%)

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%

Infant 　　　　　 Adult

Sevoflurane

(%)

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 ChargeOrser 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.

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cDNA

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mRNAmRNA

cDNA

神経受容体発現と電気生理学的測定神経受容体発現と電気生理学的測定

２電極電位固定２電極電位固定法法

Xenopus Xenopus oocyteoocyte

に組み込ﾌﾟﾗｽﾐﾄﾞに組み込ﾌﾟﾗｽﾐﾄﾞみみ

大腸菌内で大大腸菌内で大量に増殖量に増殖

プラスミドを収プラスミドを収穫し，制限酵素穫し，制限酵素で直線化で直線化

部位ﾌﾟﾛﾓｰﾀｰ部位ﾌﾟﾛﾓｰﾀｰより翻訳より翻訳

ｱﾌﾘｶﾂﾒｶﾞｴﾙｱﾌﾘｶﾂﾒｶﾞｴﾙ卵へ注入卵へ注入

24-4824-48 時間培時間培養養

Rudolph & Antkowiak: Nature Reviews Neuroscience 5: 709, 2004 より引用

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

Effects of Volatile Anesthetics on Ligand-gated Ion ChannelsEffects of Volatile Anesthetics on Ligand-gated Ion Channels

　　

　サブタイプ

Halothane Isoflurane Sevoflurane

5-HT3 受容体

　　　 5-HT3A

Potentiation Potentiation Inhibition

神経性

α4

β2Inhibition Inhibition Inhibition

nACh 受容体 α7 Inhibition No effect

骨格筋 αβγδ

Little inhibition

Little inhibition

Little inhibition

GABAA 受容体

Potentiation Potentiation Potentiation

NMDA 受容体 Inhibition Inhibition InhibitionMachu et al. J Pharmacol Exp Ther Machu et al. J Pharmacol Exp Ther

19941994Jenkins et al. Br J Pharmacol 1996Jenkins et al. Br J Pharmacol 1996Violet JM et al. Anesthesiology 1997

Flood P et al. Anesthesiology 1997Jenkins A et al. Anesthesiology 1999Hollmann MW et al. Anesth Analg 2001

Effects of Gaseous Anesthetics on Ligand-gated Ion ChannelsEffects of Gaseous Anesthetics on Ligand-gated Ion Channels

　　

　サブタイプ

N2O Xe

5-HT3 受容体

　　　 5-HT3A

Inhibition Inhibition

神経性

α4β2 Inhibition Inhibition

nACh 受容体 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 2000Yamakura et al. Anesthesiology 2000

Suzuki et al. Anesth Analg 2003Suzuki et al. Anesth Analg 2003