Why Anesthesia Is One of the Greatest Medical Mysteries of Our Time

Anesthesia was a major medical breakthrough, allowing us to lose consciousness during surgery and other painful procedures. Trouble is, we're not entirely sure how it works. But now we're getting closer to solving its mystery — and with it, the mystery of consciousness itself.

When someone goes under, their cognition and brain activity continue, but consciousness gets shut down. For example, it has been shown that rats can 'remember' odor experiences while under general anesthesia. This is why anesthesiologists, like the University of Arizona's Stuart Hameroff, are so fascinated by the whole thing.

"Anesthetics are fairly selective, erasing consciousness while sparing non-conscious brain activity," Hameroff told io9. "So the precise mechanism of anesthetic action should point to the mechanism for consciousness."

The Perils of Going Under

The odds of something bad happening while under anesthetic are exceedingly low. But this hasn't always been the case.

Indeed, anesthesiology has come a long way since that historic moment back in 1846 when a physician at Massachusetts General Hospital held a flask near a patient's face until he fell unconscious.

Related: The history of anesthesia

But as late as the 1940s, anesthesia still remained a dicey proposition. Back then, one in every 1,500 perioperative deaths were attributed to anesthesia. That number has improved dramatically since that time, mostly on account of improved techniques and chemicals, modern safety standards, and an influx of accredited anesthesiologists. Today, the chances of a healthy patient suffering an intraoperative death owing to anesthesia is less than 1 in 200,000. That's a 0.0005% chance of a fatality — which are pretty good odds if you ask me (especially if you consider the alternative, which is to be awake during a procedure).

It should be pointed out, however, that "healthy patient" is the operative term (so to speak). In actuality, anesthesia-related deaths are on the rise, and the aging population has a lot to do with it. After decades of decline, the worldwide death rate during anesthesia has risen to about 1.4 deaths per 200,000. Alarmingly, the number of deaths within a year after general anesthesia is disturbingly high — about one in every 20. For people above the age of 65, it's one in 10. The reason, says anesthesiologist André Gottschalk, is that there are more older patients being operated on. Anesthesia can be stressful for older patients with heart problems or high blood pressure.

Why Anesthesia Is One of the Greatest Medical Mysteries of Our Time

(Tyler Olson/Shutterstock)

But there are other dangers associated with anesthesia. It can induce a condition known as postoperative delirium, a state of serious confusion and memory loss. Following surgery, some patients complain about hallucinations, have trouble responding to questions, speak gibberish, and forget why they're in the hospital. Studies have shown that roughly half of all patients age 60 and over suffer from this sort of delirium. This condition usually resolves after a day or two. But for some people, typically those over the age of 70 and who have a history of mental deficits, a high enough dose of anesthesia can result in lingering problems for months and even years afterward, including attention and memory problems.

Researchers speculate that it's not the quality of the anesthetics, but rather the quantity; the greater the amount, the greater the delerium. This is not an easy problem to resolve; not enough anesthesia can leave a patient awake, but too much can kill. It's a challenging balance to achieve because, as science writer Maggie Koerth-Baker has pointed out, "Consciousness is not something we can measure."

Rots the Brain

Deep anesthesia has also been linked to other cognitive problems. New Scientist reports:

Patients received either propofol or one of several anesthetic gases. The morning after surgery, 16 percent of patients who had received light anesthesia displayed confusion, compared with 24 percent of the routine care group. Likewise, 15 percent of patients who received typical anesthesia had postoperative mental setbacks that lingered for at least three months—they performed poorly on word-recall tests, for example—but only 10 percent of those in the light anesthesia group had such difficulties.

To help alleviate these effects, doctors are encouraged to talk to their patients during regional anesthesia, and to make sure their patients are well hydrated and nourished before surgery to improve blood flow to the brain.

But just to be clear, the risks are slight. According to the Mayo Clinic:

Most healthy people don't have any problems with general anesthesia. Although many people may have mild, temporary symptoms, general anesthesia itself is exceptionally safe, even for the sickest patients. The risk of long-term complications, much less death, is very small. In general, the risk of complications is more closely related to the type of procedure you're undergoing, and your general physical health, than to the anesthesia itself.

The Neural Correlates of Consciousness

Typically, anesthesia is initiated with the injection of a drug called propofol, which gives a quick and smooth transition into unconsciousness. For longer operations, an inhaled anesthetic, like isoflurane, is added to give better control of the depth of anesthesia.

Here's a chart showing the most common applications for anesthesia (via University of Toronto):

Why Anesthesia Is One of the Greatest Medical Mysteries of Our Time

It should really come as no surprise that neuroscientists aren't entirely sure how chemicals like propofol work. We won't truly understand anesthesia until we fully understand consciousness itself — a so-called hard problem in science. But the neuroscience of anesthesia may shed light on this mystery.

Researchers need to chart the neural correlates of consciousness (NCCs) — changes in brain function that can be observed when a person transitions from being conscious to unconscious. These NCCs can be certain brain waves, physical responses, sensitivity to pain — whatever. They just need to be correlated directly to conscious awareness.

As an aside, we'll eventually need to identify NCCs in an artificial intelligence to prove that it's sentient. And in fact, this could serve as a viable substitute to the now-outdated Turing Test.

Scientists have known for quite some time that anesthetic potency correlates with solubility in an olive-oil like environment. The going theory is that they make it difficult for certain neurons to fire; they bind to and incapacitate several different proteins on the surface of neurons that are essential for regulating sleep, attention, learning, and memory. But more than that, by interrupting the normal activity of neurons, anesthetics disrupt communications between the various regions of the brain which, together, triggers unconsciousness.

Cognitive Dissonance

But neuroscientists haven't been able to figure out which region or regions of the brain are responsible for this effect. And indeed, there may be no single switch, particularly if the "global workspace" theory of consciousness continues to hold sway. This school of thought holds that consciousness is a widely distributed phenomenon where initial incoming sensory information gets processed in separate regions of the brain without us being aware of it. Subjectivity only happens when these signals are broadcast to a network of neurons disbursed throughout the brain, which then start firing in synchrony.

Why Anesthesia Is One of the Greatest Medical Mysteries of Our Time

(New Scientist)

But the degree of synchrony is a very carefully calibrated thing — and anesthetics disrupt this finely tuned harmony.

Indeed, anesthetics may be eliciting unconsciousness by blocking the brain's ability to properly integrate information. Synchrony between different areas of the cortex (the part of the brain responsible for attention, awareness, thought, and memory), gets scrambled as consciousness fades. According to researcher Andres Engels, long-distance communication gets blocked, so the brain can't build the global workspace. He says "It's like the message is reaching the mailbox, but no one is picking it up." Propofol in particular appears to cause abnormally strong synchrony between the primary cortex and other brain regions — and when too many neurons fire in a strongly synchronized rhythm, there's no room for exchange of specific messages.

Rebooting the Global Workspace

There's also the science of coming out of unconsciousness to consider. A new study shows it's not simply a matter of the anesthetic "wearing off."

Researchers from UCLA say the return of conscious brain activity occurs in discrete clumps, or clusters — and that the brain does not jump between all of the clusters uniformly. In fact, some of these activity patterns serve as "hubs" on the way back to consciousness.

"Recovery from anesthesia, is not simply the result of the anesthetic 'wearing off' but also of the brain finding its way back through a maze of possible activity states to those that allow conscious experience," noted researcher Andrew Hudson in a statement. "Put simply, the brain reboots itself."

Relatedly, a separate study from 2012 suggested that post-surgery confusion is the brain reverting to a more primitive evolutionary state as it goes through the "boot-up" process.

Quantum Vibrations in Microtubules?

There's also the work of Stuart Hameroff to consider, though his approach to consciousness is still considered speculative at this point.

He pointed me to the work of the University of Pennsylvania's Rod Eckenhoff, who has shown that anesthetics act on microtubules — extremely tiny cylindrically shaped protein polymers that are part of the cellular cytoskeleton.

Why Anesthesia Is One of the Greatest Medical Mysteries of Our Time

Jeffrey81/Wikimedia Commons

"That suggests consciousness derives from microtubules," Hameroff told io9.

Along with Travis Craddock, he also thinks that anesthetics bind to and affect cytoskeletal microtubules — and that anesthesia-related cognitive dysfunction is linked to microtubule instability. Craddock has found 'quantum channels' of aromatic amino acids in a microtubule subunit protein which regulates large scale quantum states and bind anesthetics.

I asked Hameroff where neuroscientists should focus their efforts as they work to understand the nature of consciousness.

"More studies like those of Anirban Bandyopadhyay at NIMS in Tsukuba, Japan (and now at MIT) showing megahertz and kilohertz vibrations in microtubules inside neurons," he replied. "EEG may be the tip of an iceberg of deeper level, faster, smaller scale activities in microtubules. But they're quantum, so though smaller, are non-local, and entangled through large regions of brain or more."

Indeed, brain scans of various sorts are definitely the way to go, and not just for this particular line of inquiry. It will be through the ongoing discovery of NCCs that we may eventually get to the bottom of this thing called consciousness.

Sources: ASA | Scientific American | Mayo Clinic | TIME | University of Toronto Department of Anesthesia | NYT | New Scientist

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