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42 THE SCIENTIST | the-scientist.com

hypothesis. Then, Nicholas Franks and

William Lieb of Imperial College London

showed that the true targets of anesthetic

drugs were neuronal receptors embedded

in the membrane.^3

Neuronal receptors regulate the

probability that neurons will fire action

potentials, often by acting to control

channels for specific ions to go into

and out of nerve cells. Activating excit-

atory receptors increases a neuron’s fir-

ing potential, while activating inhibitory

receptors decreases it. Hence, anesthetic

drugs could, in principle, be grouped

into two main classes: those that activate

inhibitory receptors and those that inac-

tivate excitatory receptors. (See illustra-

tion on page 40.)

Inhaled ether derivatives and intrave-

nous propofol, the most widely used anes-

thetic drug, bind to the inhibitory GABAA

receptor. Under normal, physiologi-

cal conditions, the receptor is activated

by gamma-aminobutyric acid (GABA)

released from inhibitory neurons, and it

allows the flow of chloride ions into the

cell, dropping the relative voltage of the

neuron’s interior and thereby decreasing

the probability of firing an action poten-

tial. Anesthetic drugs that target this

receptor act as agonists to promote the

influx of chloride ions, further suppress-

ing the cell’s ability to fire.

Other anesthetics such as ketamine,

which was synthesized in 1962, and nitrous

oxide block the channel of the N-methyl

D-aspartate (NMDA) glutamate receptor.

Normally activated by the neurotransmit-

ter glutamate released from excitatory

neurons, the NMDA receptor allows the

flow of potassium ions out of the cell and

calcium and sodium ions in, increasing the

relative voltage of the neuron’s interior and

thereby increasing the probability of fir-

ing an action potential. Anesthetic drugs

that target this receptor act as antagonists

to block these ions fluxes, decreasing the

ability of the cell to fire.

Knowing the actions of anesthetic

drugs on the receptors still does not fully

explain how unconsciousness occurs,

however. Both GABA and NMDA recep-

tors are found on the excitatory and

inhibitory neurons that make up neu-

ronal circuits. The function of these cir-

cuits and their relationship to behavior

can be understood within the framework

of systems neuroscience: the changes in

ion fluxes produced by anesthetic binding

to receptors dramatically alters neuronal

activity across the brain, eliciting highly

structured oscillations. In humans, these

oscillations are readily visible in the EEG

readouts. They are of high amplitude and

lie within well-defined frequency bands

lower than those of unstructured, low-

amplitude oscillations seen in the brain

of a conscious person.

The observed waves depend critically

on which receptors are bound and how the

targeted regions are connected to other

areas of the brain. The oscillations change

systematically with anesthetic drug class,

drug dose, and patient age. For example,

alpha oscillations (8–12 Hz) produced by

GABAergic anesthetics depend critically

on excitatory and inhibitory connections

between the thalamus and the cortex.^4

The beta/gamma oscillations (15–50 Hz)

produced by ketamine^5 might depend on

blocking the NMDA receptors of inhibi-

tory and excitatory neurons in the cortex,

while the slow oscillations produced by

both GABA agonists6,7 and NMDA antag-

onists might depend on inhibition of the

brainstem and its projections to the thal-

amus and cortex (See illustration on page

41.) In elderly patients the oscillations

have lower amplitudes across all frequency

bands. These oscillations also dramatically

alter when neurons can spike, and impede

communication between brain regions

that play a role in consciousness.

The characteristics of the oscilla-

tions produced by anesthetics suggest

that they are a significant part of the

mechanism of anesthetic action, and

explain how the brain state of a patient

under general anesthesia can be reli-

ably tracked using the EEG. However,

monitoring brain activity has not been

standard in anesthesiology practice.

The early attempts to use EEG as an

additional piece of information to mon-

itor patients and inform the dose and

rate of anesthetic delivery focused on

developing an index that would pro-

vide a single readout of anesthetic state.

However, EEG activity observed during

general anesthesia is different across

people of different ages, and these

indices can be misleading when used

in children or elderly people. Further-

more, EEGs captured under general

anesthesia differ across drugs, and

aggregated indices cannot take these

differences into consideration.

For those reasons, in the last few years

anesthesiologists have begun to monitor

EEG readouts of brain signals during pro-

cedures involving general anesthesia. The

oscillation patterns for common anesthet-

ics are identifiable to the trained eye, and

the assessment of their frequencies can

be performed in real time with computer

aid, providing a more nuanced picture of a

patient’s brain state. This has allowed cli-

nicians to manage anesthetic drug dosing

in a more nuanced way and to reduce the

amount of anesthesia required to achieve

the same anesthetic state.^8 As we under-

stand more about how anesthetics work,

and gain more experience directly observ-

ing EEGs generated during anesthesia, the

practice will continue to be improved.

General anesthesia as treatment

In the last several decades, research on

brain activity patterns and general anes-

Anesthetic-induced oscillations dramatically

alter when neurons can spike, and impede

commu nication between brain regions that

play a role in consciousness.