Anesthesia.. How does it make us lose consciousness?

Mark
Written By Mark

There are many drugs that anesthesiologists can use to make patients lose consciousness, but an important question that comes to mind for researchers is: How exactly do these drugs cause the brain to lose consciousness?

That’s what neuroscientists at MIT have been studying for a common drug used in anesthesia. Using a new technique to analyze the activity of neurons, the scientists discovered that the drug propofol induces unconsciousness by disrupting the brain’s natural balance between stability and excitation. The drug causes brain activity to become increasingly unstable until consciousness is lost.

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“The brain has to operate on this sharp edge between excitement and chaos,” says Earl K. Miller, the Picower Professor of Neuroscience and a member of the Picower Institute for Learning and Memory at MIT, and one of the study’s lead researchers. “It has to be excited enough for its neurons to influence each other, but if it gets too excited, it spins into chaos. Propofol seems to disrupt the mechanisms that keep the brain in this narrow range of operation.”

The results of the new study, published in the journal Neuron on July 15, could help researchers develop better tools for monitoring patients while they are under general anesthesia.

Is it excitement or stability?

Propofol is a drug that binds to receptors in the brain called GABA receptors, which inhibits the nerve cells that contain these receptors. Other anesthetics act on different types of receptors, and the mechanism by which all of these drugs produce loss of consciousness is not fully understood.

The researchers hypothesized that propofol—and perhaps other anesthetics—interfere with a brain state known as “dynamic stability,” in which neurons are excited enough to respond to new inputs, but the brain can quickly regain control and prevent them from becoming overexcited.

Previous studies on how anesthetics affect this balance have found conflicting results. Some studies have suggested that the brain becomes too stable and unresponsive during anesthesia, leading to loss of consciousness, while other studies have found that the brain becomes too excited, leading to a chaotic state that results in loss of consciousness.

Part of the reason for these conflicting results is the difficulty of accurately measuring dynamic stability in the brain. Measuring dynamic stability with loss of consciousness helps researchers determine whether loss of consciousness results from too much stability or too little stability.

In the new study, the researchers analyzed electrical recordings made in the brains of animals that received propofol over the course of an hour, during which they gradually lost consciousness. The researchers were able to measure how the brain responded to sensory inputs, such as sounds, or to spontaneous disturbances in neural activity.

Normally, the brain’s neural activity responds to any input and then returns to its baseline activity level. However, once the propofol dose was started, the brain took longer to return to baseline after these inputs, and remained in a hyperexcitable state. This phenomenon became more pronounced until the animals lost consciousness.

This suggests that inhibition of neuronal activity by propofol leads to increased instability, causing the brain to lose consciousness, the researchers said.

Improve anesthesia control

To see if they could replicate this effect in a computational model, the researchers created a simple neural network. When they increased the inhibition of some nodes in the network, as propofol does in the brain, the network’s activity became unstable, similar to the unstable activity the researchers saw in the brains of animals that had received propofol.

“We looked at a simple circuit model of interconnected neurons, and when we increased inhibition, we saw instability,” says Adam Eisen, an MIT graduate student and postdoctoral researcher at MIT and one of the study’s authors. “So one of the things we’re suggesting is that increasing inhibition can generate instability, and that’s associated with loss of consciousness.”

Researchers suspect that other anesthetics, which act on different types of neurons and receptors, may have the same effect through different mechanisms, a possibility the researchers are now studying.

If this turns out to be true, it could be useful to researchers’ ongoing efforts to develop ways to more precisely control the level of anesthesia a patient is under. These systems—which Miller, mentioned earlier, is working on with Emery Brown, a professor of biomedical engineering at MIT—work by measuring brain dynamics and then adjusting drug doses accordingly in real time.

“If you find common mechanisms that work across different anesthetics, you can make them all safer by tweaking a few buttons, rather than having to develop safety protocols for each different anesthetic,” Miller says. “We don’t want a different system for every anesthetic they use in the operating room, we want one system that fits all.”

The researchers also plan to apply their technique to measure dynamic stability in other brain conditions, including neuropsychiatric disorders.

“This method is so powerful, I think it will be very exciting to apply it to different brain conditions, different types of anesthesia, and also other neuropsychiatric disorders like depression and schizophrenia,” says Ella Vitti, professor of brain and cognitive sciences, director of the Key Lisa Yang Center for Computational Integration in Neuroscience, a member of the McGovern Institute for Brain Research at MIT, and one of the study’s principal investigators.