By Carl June
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Today anesthetics are considered as routine as a trip to the dentist. They have been around at least since the 18th century when a talented chemist named Humphry Davy discovered the mysterious effect of nitrous oxide (laughing gas). Davy, young and ambitious, set out to rigorously test the gas's effect, inhaling nitrous oxide daily for several months. Under slightly less rigorous conditions, Davy shared the gas with a distinguished group of friends including Samuel Taylor Coleridge, James Watt, and Robert Southey--who wrote in a letter that "the atmosphere of the highest of all possible heavens must be composed of this gas." These early trials laid the foundation for anesthesia's emergence in medicine today. Yet in the modern era, despite tremendous advances in the quality and selectivity of anesthetics, we still have a poor understanding of how anesthetics work in the brain.
Highlighting these fundamental gaps in knowledge, a group of researchers recently made a surprising discovery about how we transition out of consciousness and back. The common view holds that going under (induction) and coming back up (emergence) are the same process, albeit in different directions. However, a recent study published in the journal PLoS ONE suggests that going under is not the same as coming back up.
The researchers, led by Dr. Max Kelz at the University of Pennsylvania School of Medicine, observed that less anesthetic is required to keep the brain anesthetized than to induce unconsciousness. To explain these observations, the researchers have introduced a concept they call "neural inertia," referring to the brain's resistance to transitions between consciousness and unconsciousness. Elucidating the mechanisms of neural inertia could be critical to the task anesthesiologists perform every day, namely preventing patients from experiencing pain or awareness during surgery and in helping those patients who exhibit delays returning to the conscious state. This line of research could also provide insights into disrupted states of consciousness like coma.
According to the common model, an anesthetic drug reaches its site of action in the central nervous system, causing the patient to become unconscious. Over time, as the anesthetic is passively eliminated from the system, the patient comes back up. If this assumption is true then concentrations of anesthetic should be the same at entrance and emergence. Researchers performed a simple experiment in mice and fruit flies to test this idea. They measured the concentration of anesthetic in the brain going under and the concentration in the brain coming back up from the anesthetized state. They found that the concentration of anesthetic at emergence was lower than the concentration entering the anesthetized state --indicating a delay in, or resistance to, returning to the waking state.
Clinical observations in humans also provide evidence for neural inertia. Narcolepsy with cataplexy is a sleep disorder marked by intense daytime sleepiness coupled with sudden losses of muscle tone. These patients can take as long as eight hours to emerge from general anesthesia, whereas the typical patient emerges in minutes. Their disorder is known to be caused by reduced amounts of a protein called hypocretin, which helps regulate wakefulness and REM sleep. In another experiment, the researchers tested mice with mutations in a hypocretin gene causing sleep disturbances similar to humans with narcolepsy. The mutant mice did indeed show a significant delay in emerging from unconsciousness, but no difference entering into the anesthetized state, indicating that only emergence is dependent on the hypocretin system.
Research efforts are just beginning to illuminate the neural circuits underlying neural inertia, but they have the potential to make a significant impact on the field. As an anesthesiologist, Dr. Kelz sees a key function of neural inertia, namely keeping the patient unconscious. A small percentage of patients report experiencing awareness during surgery--estimates are low (around 1 in 1000 cases), but significant if you consider the number of patients who undergo general anesthesia every day. On the other end of the spectrum, patients with certain neurological conditions may not wake up for an extended period after general anesthesia. Future investigations of the circuits involved in neural inertia may give the anesthesiologist more control over anesthesia at the bedside.
A recent article in the New York Times Magazine described a series of astonishing cases in which doctors successfully woke some patients from coma after years of unresponsiveness. The discovery came accidentally when a coma patient was given an insomnia drug to improve sleep quality. To everyone's surprise, the patient woke up and recognized his mother after three years of unresponsiveness. Since the discovery, subsequent investigations have yielded similar effects in a subset of patients declared vegetative. While the effects are temporary, with continued use some patients have fully regained consciousness. Nobody understands exactly how the insomnia drugs work for these patients, but studies that begin to untangle the complex biology of neural inertia may help illuminate the transitions between conscious states that most of us take for granted.