It's arguably the biggest unanswered question in all of biology: What does it mean to be conscious? How do our physical brains, the most complex biological systems we know of, produce the sense of awareness and "self" that we experience every waking moment? Theories abound, but empirical evidence for neural pathways that may be involved in consciousness is just beginning to trickle in. And some of it is from looking at its flip side, lack of consciousness.
Unconsciousness takes different forms: sleep; coma; minimally conscious states (where patients are semi-responsive to stimuli); and the lack of awareness that anesthesia drugs induce, where surgeons can slice open tissue and perform what should be painful operations on the human body without any reaction from the patient. Although some form of anesthetic drug has been in use by surgeons for more than 150 years, there is still much to learn about how these drugs act in the brain.
Emery Brown, an anesthesiologist at Massachusetts General Hospital and Harvard Medical School and professor in the MIT department of brain and cognitive sciences, studies the brain under anesthesia, using patients with epilepsy who have had electrodes implanted to record seizure activity. When the patients are put under general anesthesia using the drug propofol (to remove the electrodes and treat the brain by removing the seizure-prone areas), Brown records the electrical activity of neurons in the brain as they "go under."
In a study published in PNAS in December 2012, he and his colleagues, including Patrick Purdon, an anesthesiologist at Massachusetts General Hospital and Harvard Medical School, asked patients to answer yes or no questions as they began to lose consciousness because of anesthesia. They looked at what was happening in the brain at the moment that the patients became unable to answer their questions — the point at which, ostensibly, they went from a conscious state to unconsciousness.
"What we saw is that right at this moment, these very profound, slow-wave oscillations appear," says Brown. "These look a lot like slow-wave sleep. They aren't subtle. And they're happening all over the cortex." These slow waves, or oscillations, act as a gate: Neurons can only fire when the oscillations are in a "down" phase of the wave. The team compared readings from areas within two centimeters of each other in the cortex and found that the slow-wave oscillations between the areas were in phase with each other; farther than 2 cm apart, the oscillations were out of phase. Neural communication can't happen between two areas that are out of phase due to the gating effect.
"You're limited to local communication," explains Brown. "If intracortical communication is necessary for consciousness, this gives you a fairly good idea of why the drug makes you unconscious." Under the influence of propofol, the slow oscillations seem to fragment communication across the brain, preventing it from synchronizing information.
This finding matches with a model of consciousness called the integrated information theory. Developed by Giulio Tonon at the University of Wisconsin, the model considers consciousness as an experience of the merging and integration of an array of tiny bits of information filtering through our brains. The unconscious state, then, occurs when the integration no longer happens. There may be local activity, like the locally synced slow-wave oscillations that Brown and Purdon saw, but the different areas of the brain are no longer communicating with each other. This theory is very young, and Tononi and other researchers continue to probe how the brain regulates levels of awareness and consciousness, as well as how consciousness turns to unconsciousness, whether in anesthesia or in coma.
Nicholas Schiff, a neurologist with Weill Cornell Physicians and a Dana Foundation grantee, studies recovery of consciousness after severe brain injury. After a severe brain injury, patients typically spend time in coma, and may next ascend to a vegetative state, where they are able to regulate breathing and other basic brain stem functions such as heart rate, and may open their eyes at times, but are unresponsive to other stimuli. Or they may enter a minimally conscious state, where they show some definite, yet irregular, behaviors in response to the world around them.
There are some commonalities between what happens in the brain during anesthesia, coma, and sleep. "If you have a normal brain, and you start to globally reduce activity in the brain, there are some rules as to how the pattern or flow of activity in the brain changes," he says. As a process, though, sleep is distinct because it is controlled by a finely tuned, highly evolved regulatory system, while coma due to brain injury and anesthesia are blunt changes to the brain. Watching what happens as patients recover from brain injury, Schiff has begun to piece together which circuits are required for the brain come back "online" (into full consciousness) following brain injury. He has proposed a model called the "mesocircuit," involving the central thalamus, the striatum, and the prefrontal cortex. There are many connections between the thalamus and the cortex, and some between the striatum and the thalamus via another structure called the global pallidus interna. There is also a connection that goes one way from the frontal cortex to the striatum, which allows the striatum to powerfully inhibit activity from the thalamus to the cortex, typically for a very short time.
"In an injured brain that isn't getting very much input to the frontal cortex," says Schiff, "because of the way the cells in the striatum work, the communication between the thalamus and the frontal cortex will start to sputter." A powerful feedback loop can take hold, further inhibiting the thalamus and the frontal cortex.
This model also takes advantage of the odd effect that anesthesiologists call paradoxical excitation. When patients are given a very low dose of anesthesia, the brain gets excited, more active, rather than being suppressed. Schiff thinks a similar mechanism might underlie something that happens for some patients with brain injury: When they are given a low dose of zolpidem, a drug used to induce sleep, they instead increase in responsiveness and level of consciousness. Schiff posits that zolpidem, known to inhibit the global pallidus interna, helps to break the inhibitory feedback loop that keeps the thalamus from sending information to the frontal cortex.
As neuroscientist continue to tease apart the anatomical structures, pathways, and circuits that underlie the experience of unconsciousness, they hope to understand better the complex network that produces the sense of awareness that so many of us take for granted each day.
"Information doesn't just flow through a brain like cars down a highway," says Brown. "It creates all kinds of loops, some excitatory, some inhibitory, some that amplify, down-regulate or modify other circuits."