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“I just couldn't wake up.” It sounds like the classic excuse for arriving late to work. But anesthesiologist Max Kelz and colleagues at the University of Pennsylvania have found evidence that our brains contain a stark barrier to changes in arousal states—from wakefulness to unconsciousness or back the other way. They dubbed this phenomenon “neural inertia.” Understanding this property of the brain might shed light on the distressing propensity of some people to wake too early from anesthesia.

Kelz became interested in sleep neurobiology when a patient of his took eight hours to awaken after a standard anesthetic procedure. In 2008 he discovered that he could mimic his patient’s predicament in mice by impairing the signaling function of a neuropeptide hormone associated with wakefulness called orexin (also known as hypocretin). If waking and...

Just as agar at 60 °C can be a liquid or a solid depending on whether it’s being warmed up or cooled down, says Kelz, the brain’s state of arousal depends on its previous state of activity. In the context of anesthetics, this means that waking does not simply result from the drug vacating the neuroreceptors upon which it acts, as some researchers had previously posited. In what Faculty Member Tony Absalom, an anesthesiologist at the University Medical Center Groningen in the Netherlands calls “a really clever study,” Kelz’s group used two different anesthetic gases to show that mice did not wake up until the brain concentration of either drug fell far below the amount required to put them to sleep. It was not sufficient merely to clear the brain’s receptors of anesthetic gas; some other process prevented the mice from waking up. Similarly, the researchers found that it took two and a half times more anesthetic gas to knock out fruit flies than was present in their bodies when they awoke. Because anesthetic gas enters the fly brain almost instantaneously and is cleared equally quickly, the delay in waking could not be due to slow diffusion of gas molecules away from neuroreceptors.

Andrzej Krauze

Kelz was surprised to discover this evidence of neural inertia, so with Steven Thomas, also at Penn, he set out to find more. The two examined mice lacking the adrenergic neurotransmitters norepinephrine and epinephrine. They found that the animals easily entered an anesthetized state, and didn’t wake up until the anesthetic was almost completely dispersed. Kelz was able to restore a wild-type level of inertia by injecting norepinephrine directly into the central nervous system. Then, with another Penn colleague, Amita Sehgal, he studied a Drosophila mutant that sleeps less than normal (an insomniac fly) and is harder to anesthetize. They found that these flies awoke from anesthesia much earlier than wild-type flies. The results of these experiments suggest a genetic component to neural inertia patterns, especially the rate of emergence from an unconscious state.

Kelz wonders if a similar mutation in humans could predispose individuals to awareness under general anesthesia. Of the 21 million people who undergo general anesthesia in the United States each year, around 20,000 to 40,000 experience some kind of awareness during surgery. Might some of these people carry a mutation similar to that of the insomniac flies?

Anesthetist and Faculty Member Michael Avidan thinks there are already enough reasons to consider genotyping patients before surgery to determine sensitivity to drugs or potential to suffer dangerous side effects. Determining in advance whether an anesthetized patient is likely to become aware—or to experience delayed emergence and enter a coma—would be a major advance in surgical safety.

Avidan points out that the concept of neural inertia is still controversial, and we don’t yet know the mechanisms driving the phenomenon. But he believes that research like Kelz’s can not only improve patient care, but also give insights into such “profound mysteries” as the nature of consciousness and why we sleep. Kelz is trying to map neural circuits in the Drosophila brain that modulate the height of the barrier between consciousness and unconsciousness, and he's collaborating with first author Eliot Friedman, in Penn's Division of Sleep Medicine, on screens to identify the genes behind neural inertia.

The Hidden Jewel describes a recent paper from a specialized journal, selected by the Faculty. You can read the review of Kelz's article here.

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