This is how anesthesia drugs work to induce unconsciousness

There are many drugs that anesthesiologists use to induce unconsciousness in patients. Understanding how these drugs cause the brain to lose consciousness has been a longstanding question. MIT neuroscientists have now answered this question for the commonly used anesthesia drug, propofol.

Using a novel technique to analyze neuron activity, researchers discovered that propofol induces unconsciousness by disrupting the brain’s balance between stability and excitability. The drug causes brain activity to become increasingly unstable, leading to unconsciousness.

“The brain has to operate on this knife’s edge between excitability and chaos. It’s got to be excitable enough for its neurons to influence one another, but if it gets too excitable, it spins off into chaos. Propofol seems to disrupt the mechanisms that keep the brain in that narrow operating range,” says Earl K. Miller, the Picower Professor of Neuroscience and a member of MIT’s Picower Institute for Learning and Memory.

The new findings, set to appear in Neuron, could help researchers develop better tools for monitoring patients undergoing general anesthesia.

Miller and Ila Fiete, a professor of brain and cognitive sciences, the director of the K. Lisa Yang Integrative Computational Neuroscience Center (ICoN), and a member of MIT’s McGovern Institute for Brain Research, are the senior authors of the new study. MIT graduate student Adam Eisen and MIT postdoc Leo Kozachkov are the lead authors.

Propofol binds to GABA receptors in the brain, inhibiting neurons with those receptors. Other anesthesia drugs act on different types of receptors, and the full mechanism by which all these drugs produce unconsciousness is not fully understood.

Miller, Fiete, and their students hypothesized that propofol, and possibly other anesthesia drugs, interfere with a brain state known as “dynamic stability.” In this state, neurons are excitable enough to respond to new input, but the brain can quickly regain control and prevent them from becoming overly excited.

Previous studies on how anesthesia drugs affect this balance have yielded conflicting results. Some suggested that during anesthesia, the brain becomes too stable and unresponsive, leading to unconsciousness. Others found that the brain becomes too excitable, resulting in a chaotic state that causes unconsciousness.

One reason for these conflicting results is the difficulty in accurately measuring dynamic stability in the brain. Measuring dynamic stability as consciousness is lost would help researchers determine if unconsciousness results from too much stability or too little.

In this study, researchers analyzed electrical recordings made in the brains of animals receiving propofol over an hour-long period, during which they gradually lost consciousness. The recordings were made in four brain areas involved in vision, sound processing, spatial awareness, and executive function.

These recordings covered only a small fraction of the brain’s overall activity. To overcome this limitation, the researchers used a technique called delay embedding. This technique allows characterization of dynamical systems from limited measurements by augmenting each measurement with previously recorded ones.

Using this method, the researchers quantified how the brain responds to sensory inputs, such as sounds, or to spontaneous perturbations of neural activity.

In the normal, awake state, neural activity spikes after any input, then returns to its baseline activity level. However, once propofol dosing began, the brain took longer to return to its baseline after these inputs, remaining in an overly excited state. This effect became more pronounced until the animals lost consciousness.

This suggests that propofol’s inhibition of neuron activity leads to escalating instability, causing the brain to lose consciousness, the researchers say.

To replicate this effect in a computational model, the researchers created a simple neural network. When they increased the inhibition of certain nodes in the network, as propofol does in the brain, network activity became destabilized, similar to the unstable activity observed in the brains of animals receiving propofol.

“We looked at a simple circuit model of interconnected neurons, and when we turned up inhibition in that, we saw a destabilization. So, one of the things we’re suggesting is that an increase in inhibition can generate instability, and that is subsequently tied to loss of consciousness,” Eisen says.

As Fiete explains, “This paradoxical effect, in which boosting inhibition destabilizes the network rather than silencing or stabilizing it, occurs because of disinhibition. When propofol boosts the inhibitory drive, this drive inhibits other inhibitory neurons, and the result is an overall increase in brain activity.”

The researchers suspect that other anesthetic drugs, which act on different types of neurons and receptors, may converge on the same effect through different mechanisms — a possibility they are now exploring.

If this proves true, it could aid ongoing efforts to develop ways to more precisely control the level of anesthesia a patient experiences. These systems, which Miller is working on with Emery Brown, the Edward Hood Taplin Professor of Medical Engineering at MIT, work by measuring the brain’s dynamics and adjusting drug dosages accordingly in real-time.

“If you find common mechanisms at work across different anesthetics, you can make them all safer by tweaking a few knobs, instead of having to develop safety protocols for all the different anesthetics one at a time,” Miller says. “You don’t want a different system for every anesthetic they’re going to use in the operating room. You want one that’ll do it all.”

The researchers also plan to apply their technique for measuring dynamic stability to other brain states, including neuropsychiatric disorders.

“This method is pretty powerful, and I think it’s going to be very exciting to apply it to different brain states, different types of anesthetics, and also other neuropsychiatric conditions like depression and schizophrenia,” Fiete says.

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