There are many drugs that anesthesiologists can use to render a patient unconscious, but just how these drugs affect the brain has long been a question, and now MIT neuroscientists have answered it for one commonly used anesthetic.
Using a new technique to analyze neuronal activity, researchers discovered that the drug propofol induces unconsciousness by disrupting the brain’s normal balance of stability and excitability. The drug makes the brain’s activity increasingly unstable, until the brain loses consciousness.
“The brain has to function on a fine line between excitability and confusion: neurons need to be excitable enough to influence each other, but too excited and they get confused. Propofol appears to inhibit the mechanisms that keep the brain in that narrow operating range,” says Earl K. Miller, MIT Picower Professor of Neuroscience and member of the Picower Institute for Learning and Memory.
The new findings are Reported today NeuronResearchers may be able to develop better tools for monitoring patients undergoing general anesthesia.
Miller and Ira Fiete, professor of brain and cognitive sciences, director of the K. Lisa Yang Center for Integrative Computational Neuroscience (ICoN) and member of the MIT McGovern Institute for Brain Research, are senior authors of the new study. MIT graduate student Adam Eisen and MIT postdoctoral researcher Leo Kozatchikoff are lead authors on the paper.
lose consciousness
Propofol is a drug that binds to GABA receptors in the brain and inhibits neurons that have these receptors. Other anesthetics act on different types of receptors, but the mechanisms of how all these drugs cause loss of consciousness are not fully understood.
Miller, Fiete and their students hypothesized that propofol, and possibly other anesthetics, disrupt a brain state called “dynamic stability”: in this state, neurons are excitable enough to respond to new inputs, but the brain can quickly regain control and prevent neurons from becoming overly excited.
Previous studies of how anesthetics affect this balance have found conflicting results: Some studies suggest that during anesthesia, the brain becomes too stable, making the patient unresponsive and causing loss of consciousness, while other studies suggest that the brain becomes too excited, making the patient confused and causing loss of consciousness.
One reason for these conflicting results is the difficulty of accurately measuring the brain’s dynamic stability. By measuring dynamic stability when consciousness is lost, researchers can determine whether loss of consciousness is due to too much stability or too little stability.
In the study, the researchers analyzed electrical signals recorded over an hour in the brains of animals that were gradually rendered unconscious after receiving propofol, in four brain regions involved in vision, speech processing, spatial awareness, and executive function.
These recordings only covered a small portion of the brain’s overall activity, so to overcome that, the researchers used a technique called delayed embedding, which allows researchers to characterize a dynamical system from limited measurements by augmenting each measurement with previously recorded ones.
Using this method, the researchers were able to quantify how the brain responds to sensory inputs such as sound, as well as to spontaneous perturbations in neural activity.
“In a normal awake state, neural activity spikes after stimulation and then returns to baseline activity levels. But once propofol was administered, the brain began to take longer to return to baseline after stimulation and remained in an overly excited state. This effect became increasingly pronounced until the animals lost consciousness.”
This suggests that propofol suppresses neuronal activity, making the brain more unstable and causing a loss of consciousness, the researchers say.
Better anesthetic control
To see if they could replicate this effect in a computational model, the researchers created a simple neural network. Increasing inhibition of specific nodes in the network, just as propofol does in the brain, made the network’s activity unstable, similar to the erratic activity the researchers had observed in the brains of animals given propofol.
“We looked at a simple circuit model of interconnected neurons, and in it, increasing inhibition led to destabilization. So one of our ideas is that increased inhibition creates instability, which could lead to loss of consciousness,” Eisen says.
Fiete explains: “This paradoxical effect, in which increasing inhibition destabilizes the network rather than silences or stabilizes it, occurs through disinhibition. When propofol increases the inhibitory impulse, this impulse inhibits other inhibitory neurons, resulting in an overall increase in brain activity.”
The researchers suspect that other anesthetics that act on different types of neurons or receptors may exert the same effect through different mechanisms, and are currently investigating this possibility.
If true, this could aid researchers in their ongoing efforts to develop ways to more precisely control the level of anesthesia patients experience. These systems, which Miller is working on in collaboration with Emery Brown, the Edward Hood Taplin Professor of Medical Engineering at MIT, work by measuring brain activity and adjusting drug dosages accordingly in real time.
“Once we understand the common mechanisms across a range of anesthetic agents, we can tweak a few knobs to make them all safer. We don’t need to develop safety protocols for every agent all at once,” Miller says. “We don’t need a different system for every agent we use in the operating room. We need a system that works for them all.”
The researchers also plan to apply their technique for measuring dynamic stability to other brain conditions, including neuropsychiatric disorders.
“This method is very powerful and we think it could be very interesting to apply it to different brain states, different types of anesthetics, and even other neuropsychiatric disorders such as depression and schizophrenia,” Fiete says.
This research was funded by the Office of Naval Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Science Foundation’s Department of Computer and Information Science and Engineering, the Simons Social Brain Center, the Simons Global Brain Collaboration, the JPB Foundation, the McGovern Institute, and the Picower Institute.
