Banishing consciousness: the mystery of anaesthesia, 29 November 2011 by Linda Geddes, Magazine issue 2840.
I WALK into the operating theatre feeling vulnerable in a draughty gown and surgical stockings. Two anaesthetists in green scrubs tell me to stash my belongings under the trolley and lie down. "Can we get you something to drink from the bar?" they joke, as one deftly slides a needle into my left hand.
I smile weakly and ask for a gin and tonic. None appears, of course, but I begin to feel light-headed, as if I really had just knocked back a stiff drink. I glance at the clock, which reads 10.10 am, and notice my hand is feeling cold. Then, nothing.
I have had two operations under general anaesthetic this year. On both occasions I awoke with no memory of what had passed between the feeling of mild wooziness and waking up in a different room. Both times I was told that the anaesthetic would make me feel drowsy, I would go to sleep, and when I woke up it would all be over.
What they didn't tell me was how the drugs would send me into the realms of oblivion. They couldn't. The truth is, no one knows.
The development of general anaesthesia has transformed surgery from a horrific ordeal into a gentle slumber. It is one of the commonest medical procedures in the world, yet we still don't know how the drugs work. Perhaps this isn't surprising: we still don't understand consciousness, so how can we comprehend its disappearance?
That is starting to change, however, with the development of new techniques for imaging the brain or recording its electrical activity during anaesthesia. "In the past five years there has been an explosion of studies, both in terms of consciousness, but also how anaesthetics might interrupt consciousness and what they teach us about it," says George Mashour, an anaesthetist at the University of Michigan in Ann Arbor. "We're at the dawn of a golden era."
Consciousness has long been one of the great mysteries of life, the universe and everything. It is something experienced by every one of us, yet we cannot even agree on how to define it. How does the small sac of jelly that is our brain take raw data about the world and transform it into the wondrous sensation of being alive? Even our increasingly sophisticated technology for peering inside the brain has, disappointingly, failed to reveal a structure that could be the seat of consciousness.
Altered consciousness doesn't only happen under a general anaesthetic of course - it occurs whenever we drop off to sleep, or if we are unlucky enough to be whacked on the head. But anaesthetics do allow neuroscientists to manipulate our consciousness safely, reversibly and with exquisite precision.
It was a Japanese surgeon who performed the first known surgery under anaesthetic, in 1804, using a mixture of potent herbs. In the west, the first operation under general anaesthetic took place at Massachusetts General Hospital in 1846. A flask of sulphuric ether was held close to the patient's face until he fell unconscious.
Since then a slew of chemicals have been co-opted to serve as anaesthetics, some inhaled, like ether, and some injected. The people who gained expertise in administering these agents developed into their own medical specialty. Although long overshadowed by the surgeons who patch you up, the humble "gas man" does just as important a job, holding you in the twilight between life and death.
Consciousness may often be thought of as an all-or-nothing quality - either you're awake or you're not - but as I experienced, there are different levels of anaesthesia (see diagram). "The process of going into and out of general anaesthesia isn't like flipping a light switch," says Mashour. "It's more akin to a dimmer switch."
A typical subject first experiences a state similar to drunkenness, which they may or may not be able to recall later, before falling unconscious, which is usually defined as failing to move in response to commands. As they progress deeper into the twilight zone, they now fail to respond to even the penetration of a scalpel - which is the point of the exercise, after all - and at the deepest levels may need artificial help with breathing.
These days anaesthesia is usually started off with injection of a drug called propofol, which gives a rapid and smooth transition to unconsciousness, as happened with me. (This is also what Michael Jackson was allegedly using as a sleeping aid, with such unfortunate consequences.) Unless the operation is only meant to take a few minutes, an inhaled anaesthetic, such as isoflurane, is then usually added to give better minute-by-minute control of the depth of anaesthesia.
Lock and key
So what do we know about how anaesthetics work? Since they were first discovered, one of the big mysteries has been how the members of such a diverse group of chemicals can all result in the loss of consciousness. Other drugs work by binding to receptor molecules in the body, usually proteins, in a way that relies on the drug and receptor fitting snugly together like a key in a lock. Yet the long list of anaesthetic agents ranges from large complex molecules such as barbiturates or steroids, to the inert gas xenon, which exists as mere atoms. How could they all fit the same lock?
For a long time there was great interest in the fact that the potency of anaesthetics correlates strikingly with how well they dissolve in olive oil. The popular "lipid theory" said that instead of binding to specific protein receptors, the anaesthetic physically disrupted the fatty membranes of nerve cells, causing them to malfunction.
In the 1980s, though, experiments in test tubes showed that anaesthetics could bind to proteins in the absence of cell membranes. Since then, protein receptors have been found for many anaesthetics. Propofol, for instance, binds to receptors on nerve cells that normally respond to a chemical messenger called GABA. Presumably the solubility of anaesthetics in oil affects how easily they reach the receptors bound in the fatty membrane.
But that solves only a small part of the mystery. We still don't know how this binding affects nerve cells, and which neural networks they feed into. "If you look at the brain under both xenon and propofol anaesthesia, there are striking similarities," says Nick Franks of Imperial College London, who overturned the lipid theory in the 1980s. "They must be triggering some common neuronal change and that's the big mystery."
Many anaesthetics are thought to work by making it harder for neurons to fire, but this can have different effects on brain function, depending on which neurons are being blocked. So brain-imaging techniques such as functional MRI scanning, which tracks changes in blood flow to different areas of the brain, are being used to see which regions of the brain are affected by anaesthetics. Such studies have been successful in revealing several areas that are deactivated by most anaesthetics. Unfortunately, so many regions have been implicated it is hard to know which, if any, are the root cause of loss of consciousness.
But is it even realistic to expect to find a discrete site or sites acting as the mind's "light switch"? Not according to a leading theory of consciousness that has gained ground in the past decade, which states that consciousness is a more widely distributed phenomenon. In this "global workspace" theory, incoming sensory information is first processed locally in separate brain regions without us being aware of it. We only become conscious of the experience if these signals are broadcast to a network of neurons spread through the brain, which then start firing in synchrony.
The idea has recently gained support from recordings of the brain's electrical activity using electroencephalograph (EEG) sensors on the scalp, as people are given anaesthesia. This has shown that as consciousness fades there is a loss of synchrony between different areas of the cortex - the outermost layer of the brain important in attention, awareness, thought and memory (Science, vol 322, p 876).
This process has also been visualised using fMRI scans. Steven Laureys, who leads the Coma Science Group at the University of Liège in Wallonia, Belgium, looked at what happens during propofol anaesthesia when patients descend from wakefulness, through mild sedation, to the point at which they fail to respond to commands. He found that while small "islands" of the cortex lit up in response to external stimuli when people were unconscious, there was no spread of activity to other areas, as there was during wakefulness or mild sedation (Frontiers in Systems Neuroscience, vol 4, p 160).
A team led by Andreas Engel at the University Medical Center in Hamburg, Germany, have been investigating this process in still more detail by watching the transition to unconsciousness in slow motion. Normally it takes about 10 seconds to fall asleep after a propofol injection. Engel has slowed it down to many minutes by starting with just a small dose, then increasing it in seven stages. At each stage he gives a mild electric shock to the volunteer's wrist and takes EEG readings.
We know that upon entering the brain, sensory stimuli first activate a region called the primary sensory cortex, which runs like a headband from ear to ear. Then further networks are activated, including frontal regions involved in controlling behaviour, and temporal regions towards the base of the brain that are important for memory storage.
Engel found that at the deepest levels of anaesthesia, the primary sensory cortex was the only region to respond to the electric shock. "Long-distance communication seems to be blocked, so the brain cannot build the global workspace," says Engel, who presented the work at last year's Society for Neuroscience meeting in San Diego. "It's like the message is reaching the mailbox, but no one is picking it up."
What could be causing the blockage? Engel has unpublished EEG data suggesting that propofol interferes with communication between the primary sensory cortex and other brain regions by causing abnormally strong synchrony between them. "It's not just shutting things down. The communication has changed," he says. "If too many neurons fire in a strongly synchronised rhythm, there is no room for exchange of specific messages."
The communication between the different regions of the cortex is not just one way; there is both forward and backward signalling between the different areas. EEG studies on anaesthetised animals suggest it is the backwards signal between these areas that is lost when they are knocked out.
Last month, Mashour's group published EEG work showing this to be important in people too. Both propofol and the inhaled anaesthetic sevoflurane inhibited the transmission of feedback signals from the frontal cortex in anaesthetised surgical patients. The backwards signals recovered at the same time as consciousness returned (PLoS One, DOI:10.1371/journal.pone.0025155). "The hypothesis is whether the preferential inhibition of feedback connectivity is what initially makes us unconscious," he says.
Similar findings are coming in from studies of people in a coma or persistent vegetative state (PVS), who may open their eyes in a sleep-wake cycle, although remain unresponsive. Laureys, for example, has seen a similar breakdown in communication between different cortical areas in people in a coma. "Anaesthesia is a pharmacologically induced coma," he says. "That same breakdown in global neuronal workspace is occurring."
Many believe that studying anaesthesia will shed light on disorders of consciousness such as coma. "Anaesthesia studies are probably the best tools we have for understanding consciousness in health and disease," says Adrian Owen of the University of Western Ontario in London, Canada.
Owen and others have previously shown that people in a PVS respond to speech with electrical activity in their brain. More recently he did the same experiment in people progressively anaesthetised with propofol. Even when heavily sedated, their brains responded to speech. But closer inspection revealed that those parts of the brain that decode the meaning of speech had indeed switched off, prompting a rethink of what was happening in people with PVS (Proceedings of the National Academy of Sciences, vol 104, p 16032). "For years we had been looking at vegetative and coma patients whose brains were responding to speech and getting terribly seduced by these images, thinking that they were conscious," says Owen. "This told us that they are not conscious."
As for my own journey back from the void, the first I remember is a different clock telling me that it is 10.45 am. Thirty-five minutes have elapsed since my last memory - time that I can't remember, and probably never will.
"Welcome back," says a nurse sitting by my bed. I drift in and out of awareness for a further undefined period, then another nurse wheels me back to the ward, and offers me a cup of tea. As the shroud of darkness begins to lift, I contemplate what has just happened. While I have been asleep, a team of people have rolled me over, cut me open, and rummaged about inside my body - and I don't remember any of it. For a brief period of time "I" had simply ceased to be.
My experience leaves me with a renewed sense of awe for what anaesthetists do as a matter of routine. Without really understanding how, they guide hundreds of millions of people a year as close to the brink of nothingness as it is possible to go without dying. Then they bring them safely back home again.
Linda Geddes is a reporter at New Scientist