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Understanding Anesthesia

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Every thought travels an elaborate pathway through the brain. When the brain responds to a sight or sound, sensory impressions move directly from the optic or auditory nerve to the thalamus, the clearinghouse for sensory information. They then go to the cortex, where the electrical impulse carried by the brain’s circuitry is processed into a conscious thought—say, associating a certain sound with a particular musical instrument.

Subjects in Brown’s experiments are asked to respond to auditory stimuli. The volunteer presses a button to indicate whether a tone is high or low pitched. With the subject under a light dose of propofol, the EEG graph still shows the choppy up and down of active thought, and the subject is sufficiently alert to respond to 90% of the tones. With a moderate dose, brain waves begin to elongate, and the subject can respond to only two out of three tones. Under a heavy dose, the brain waves form long swells, and there’s no response to the tones.

Yet even then, the brain continues to process sound. The fMRI images show auditory information making its way through the thalamus to the auditory cortex. In other words, the brain still appears to recognize sound as sound, even though the subject is unconscious and will have no memory of hearing it.

More tests will be needed to establish a method to gauge how far into the cortex auditory signals advance before being snuffed out. Then, Brown and his team hope to conduct tests that substitute pain for sound. If they ultimately locate the specific regions at which anesthesia deadens pain, the next step could be to develop a drug that affects just those parts of the brain.

Brain imaging with fMRIs goes a step beyond EEGs in determining what happens when a patient is anesthetized. Yet even fMRIs can’t measure activity at its most basic level—individual neurons transmitting information.

In order to communicate with one another, brain cells release chemicals that bridge the gap between cells. Some of these agents, called neurotransmitters, are “excitatory”—that is, they pass along a call to action, while others inhibit action. “Anesthetics seem to decrease the activity of excitatory synapses, and at the same time magnify the effects of the inhibitory synapses,” says Neil Harrison, professor of pharmacology in anesthesiology at Cornell University’s Weill Medical College in New York City. The brain’s primary inhibitory transmitter is known as gamma-aminobutyric acid (GABA), and Harrison thinks that anesthetics somehow enhance the ability of GABA receptors to keep messages from making their way through the brain.

During the 1990s, to test this theory, Harrison and others added brainlike GABA receptors to human kidney cells (which have no such receptors). Then they applied GABA to the cells to imitate cell-to-cell communication and recorded the minute electrical charges that resulted. When anesthetic drugs were introduced to the cells, the electrical signals caused by GABA became stronger. Next, the researchers genetically modified the receptors so that they continued to respond to GABA but now no longer responded to anesthetics. It was a landmark finding because it supported the idea that anesthetic drugs indeed target specific receptors.

Several years later, competing researchers in Zurich and Pittsburgh bred mice with altered GABA receptors, and some of the animals proved to be up to 30 times more resistant to anesthesia than normal mice would be. Now scientists are trying to determine exactly how anesthetic drugs bind to the receptors. Unlocking that puzzle might lead to more targeted anesthetics as well as to drugs that could quickly reverse the effects of anesthesia.

As an undergraduate at Cambridge University during the early 1980s, Harrison was lured to the study of anesthesiology by how little was known. In a pharmacology course, professors provided detailed descriptions of how antibiotics and other drugs did their work. “But in the lecture on anesthetics, the whole story was so vague it didn’t make sense,” says Harrison. “The whole thing struck me as unsatisfying.”

For Harrison and others, that dissatisfaction is giving way to a sense of hope. “We have been able to figure out with great precision how the vast majority of drugs work,” says Stanford’s Steven Shafer. “I can’t think of any other conventional pharmaceutical that’s more than 10 years old for which we don’t know the mechanism of action.” Now, after 160 years, researchers may finally be on the road to solving what Shafer calls “the oldest unsolved mystery in pharmacology.

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Consciousness Unbound

Some researchers say the key to learning how anesthetics work is to examine a much tougher subject: consciousness.

Number Conscious

The bispectral index uses EEG readings to assign a number to a patient's level of consciousness, allowing doctors to administer more precise doses of anesthesia.

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hed-dossier

1.“A Primer for EEG Signal Processing in Anesthesia,” by Ira J. Rampil, Anesthesia, October 1998. A definitive if highly technical account of BIS readings and other uses of EEG in anesthesiology.

2.“The Effects of Anesthetics on Brain Activity and Cognitive Function,” by Wolfgang Heinke and Stefan Koelsch, Current Opinion in Anaesthesiology, December 2005. An excellent overview of recent work, from EEGs to neuroimaging.

3.“Consciousness Unbound,” by George A. Mashour, Anesthesiology, February 2004. A reflection on the various “cognitive binding” theories of consciousness, and their implications for anesthesia.

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