Since 1846, when a Boston dentist named William Morton gave the first public demonstration of general anesthesia using ether, scientists and doctors have tried to figure out what happens to the brain during general anesthesia.



Though much has been learned since then, many aspects of general anesthesia remain a mystery. How do anesthetic drugs interfere with neurons and brain chemicals to produce the profound loss of consciousness and lack of pain typical of general anesthesia? And, how does general anesthesia differ from sleep or coma?



Emery Brown, an MIT neuroscientist and practicing anesthesiologist at Massachusetts General Hospital, wants to answer those questions by bringing the rigorous approach of neuroscience to the study of general anesthesia. In a review article published online Dec. 29 in the New England Journal of Medicine, he and two colleagues lay out a new framework for studying general anesthesia by relating it to what is already known about sleep and coma.



Such an approach could help researchers discover new ways to induce general anesthesia, and improve our understanding of other brain states such as drug addiction, epilepsy and Parkinson’s disease, says Brown, who is a professor in the Department of Brain and Cognitive Sciences and the Harvard-MIT Division of Health Sciences and Technology.



“Anesthesia hasn’t been attacked as seriously as other questions in neuroscience, such as how the visual system works,” says Brown, who started studying general anesthesia several years ago. Neuroscientists study vision at all levels, including molecular, neurophysiological and theoretical. “Why shouldn’t we be doing the same thing for questions of general anesthesia?” he asks.



Anesthesia, sleep and coma



In the United States, 60,000 surgical patients undergo general anesthesia every day. Though doctors sometimes tell their patients that they will be “going to sleep” during a surgical procedure, that is not accurate, says Brown. “This may sound nitpicky, but we need to speak precisely about what this state is,” he says. “This paper is an attempt to start at square one and get clear definitions in place.”



General anesthesia is not simply a deep sleep, Brown emphasizes. In fact, part of the reason that he and his colleagues wrote the NEJM paper is to make doctors more aware of the differences and similarities between general anesthesia, sleep and coma. Co-author Ralph Lydic, a neuroscientist at the University of Michigan, is an expert in sleep, and Nicholas Schiff, another co-author and neurologist at Weill Cornell Medical College, is an expert in coma.



In the NEJM paper, the authors define general anesthesia as a “drug-induced, reversible condition that includes specific behavioral and physiological traits” — unconsciousness, amnesia, pain numbing, and inability to move. Also key is the stability of body functions such as respiration, circulation and temperature regulation.



Using EEG (electroencephalography) readings, which reveal electrical activity in the brain, Brown and his colleagues show that even the deepest sleep is not as deep as the lightest general anesthesia.



Throughout the night, the sleeping brain cycles through three stages of non-REM (rapid eye movement) sleep, alternating with REM sleep, which is when most dreaming occurs. Each of these has a distinctive EEG pattern. None of those resembles the EEG of a brain under general anesthesia, however. In fact, general anesthesia EEG patterns are most similar to those of a comatose brain. As Brown points out, general anesthesia is essentially a “reversible coma.”



Indeed, the early clinical signs of emergence from general anesthesia — return of regular breathing, return of movements and cognition — parallel those of recovery from a coma, though compressed over minutes instead of the hours (or even years) it takes to come out of a coma.



In addition, the paper offers explanations for the clinical signs of loss of consciousness induced by general anesthesia, based on the underlying neural circuits. The authors also explain a phenomenon known as “paradoxical excitation,” in which anesthetic drugs actually increase brain activity while inducing loss of consciousness. As one example, the authors describe how the drug ketamine produces unconsciousness by inhibiting neurons whose job is to restrain other neurons, leading to overexcitation in several brain regions. This overexcitation explains the hallucinations seen with ketamine, a common drug of abuse also known as “Special K.”



Toward better anesthetics



Though general anesthesia is seen as a routine procedure, it does hold some risk. Estimated mortality directly attributable to anesthesia is one in 250,000. The drug believed to have caused Michael Jackson’s death, propofol, is a potent anesthetic.



“Anesthetics are very powerful medications with a very narrow safety margin, as evidenced by the unfortunate events surrounding Michael Jackson’s death,” says Andreas Loepke, associate professor of clinical anesthesia and pediatrics at the University of Cincinnati College of Medicine. “These medications carry potent side effects, such as respiratory depression, loss of protective airway reflexes, blood-pressure instability, as well as nausea and vomiting.”



A better understanding of how general anesthesia works at the cellular and molecular level could help researchers develop anesthestic drugs that lack those side effects, says Loepke, who was not involved with this paper.



Brown also hopes his work will lead to new anesthetic drugs. To that end, he has several ongoing studies in which he is recording electrical activity from the brains of animals under general anesthesia, as well as imaging human brains. From these studies, he hopes to learn more about which parts of the brain become more or less active during general anesthesia.



