Anesthesiologists have long used various drugs to induce unconsciousness in patients, but the exact mechanism by which these drugs work has been unclear. MIT neuroscientists have now uncovered how the commonly used anesthesia drug propofol causes the brain to lose consciousness.
Using a novel technique to analyze neuron activity, the researchers discovered that propofol disrupts the brain's balance between stability and excitability. The drug causes brain activity to become increasingly unstable, ultimately leading to unconsciousness.
"The brain operates on a knife's edge between excitability and chaos," explains Earl K. Miller, the Picower Professor of Neuroscience and a member of MIT's Picower Institute for Learning and Memory. "Propofol seems to disrupt the mechanisms that keep the brain in that narrow operating range."
The findings, published in Neuron, may help develop better tools for monitoring patients during general anesthesia.
Miller and Ila Fiete, a professor of brain and cognitive sciences and director of the K. Lisa Yang Integrative Computational Neuroscience Center (ICoN) at MIT, are the senior authors of the study. MIT graduate student Adam Eisen and postdoc Leo Kozachkov are the lead authors.
Understanding Propofol's Effect Propofol binds to GABA receptors in the brain, inhibiting neurons with these receptors. The researchers hypothesized that propofol, and possibly other anesthesia drugs, interfere with a brain state known as "dynamic stability." This state allows neurons to respond to new input while maintaining control and preventing over-excitement.
Previous studies on anesthesia drugs' effects have produced conflicting results. Some suggested that the brain becomes too stable and unresponsive, while others found it becomes too excitable, leading to chaos.
In this study, the researchers analyzed electrical recordings from animals receiving propofol over an hour, covering brain areas involved in vision, sound processing, spatial awareness, and executive function. Using a technique called delay embedding, they quantified how the brain responds to sensory inputs and spontaneous neural activity.
In the normal awake state, neural activity spikes and returns to baseline quickly. Under propofol, the brain took longer to return to baseline, remaining overly excited until unconsciousness occurred.
Replicating the Effect To replicate this effect, the researchers created a neural network model. Increasing inhibition in the network, similar to propofol's action, destabilized activity, mirroring the observed instability in animals.
"This paradoxical effect, where boosting inhibition destabilizes the network, occurs because of disinhibition," explains Fiete. "Propofol increases inhibitory drive, which inhibits other inhibitory neurons, resulting in overall increased brain activity."
The researchers suspect other anesthetic drugs may converge on the same effect through different mechanisms and are now exploring this possibility.
Improving Anesthesia Control These findings could aid efforts to develop systems that precisely control anesthesia levels by measuring brain dynamics and adjusting dosages in real-time. Miller and Emery Brown, the Edward Hood Taplin Professor of Medical Engineering at MIT, are working on such systems.
"If common mechanisms are found across different anesthetics, safety protocols can be standardized," says Miller. "You don't want a different system for every anesthetic used in the operating room. You want one that'll do it all."
The researchers also plan to apply their technique to other brain states, including neuropsychiatric disorders like depression and schizophrenia.
"This method is powerful and exciting to apply to different brain states and conditions," says Fiete.
The 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, the Simons Center for the Social Brain, the Simons Collaboration on the Global Brain, the JPB Foundation, the McGovern Institute, and the Picower Institute.
Using a novel technique to analyze neuron activity, the researchers discovered that propofol disrupts the brain's balance between stability and excitability. The drug causes brain activity to become increasingly unstable, ultimately leading to unconsciousness.
"The brain operates on a knife's edge between excitability and chaos," explains Earl K. Miller, the Picower Professor of Neuroscience and a member of MIT's Picower Institute for Learning and Memory. "Propofol seems to disrupt the mechanisms that keep the brain in that narrow operating range."
The findings, published in Neuron, may help develop better tools for monitoring patients during general anesthesia.
Miller and Ila Fiete, a professor of brain and cognitive sciences and director of the K. Lisa Yang Integrative Computational Neuroscience Center (ICoN) at MIT, are the senior authors of the study. MIT graduate student Adam Eisen and postdoc Leo Kozachkov are the lead authors.
Understanding Propofol's Effect Propofol binds to GABA receptors in the brain, inhibiting neurons with these receptors. The researchers hypothesized that propofol, and possibly other anesthesia drugs, interfere with a brain state known as "dynamic stability." This state allows neurons to respond to new input while maintaining control and preventing over-excitement.
Previous studies on anesthesia drugs' effects have produced conflicting results. Some suggested that the brain becomes too stable and unresponsive, while others found it becomes too excitable, leading to chaos.
In this study, the researchers analyzed electrical recordings from animals receiving propofol over an hour, covering brain areas involved in vision, sound processing, spatial awareness, and executive function. Using a technique called delay embedding, they quantified how the brain responds to sensory inputs and spontaneous neural activity.
In the normal awake state, neural activity spikes and returns to baseline quickly. Under propofol, the brain took longer to return to baseline, remaining overly excited until unconsciousness occurred.
Replicating the Effect To replicate this effect, the researchers created a neural network model. Increasing inhibition in the network, similar to propofol's action, destabilized activity, mirroring the observed instability in animals.
"This paradoxical effect, where boosting inhibition destabilizes the network, occurs because of disinhibition," explains Fiete. "Propofol increases inhibitory drive, which inhibits other inhibitory neurons, resulting in overall increased brain activity."
The researchers suspect other anesthetic drugs may converge on the same effect through different mechanisms and are now exploring this possibility.
Improving Anesthesia Control These findings could aid efforts to develop systems that precisely control anesthesia levels by measuring brain dynamics and adjusting dosages in real-time. Miller and Emery Brown, the Edward Hood Taplin Professor of Medical Engineering at MIT, are working on such systems.
"If common mechanisms are found across different anesthetics, safety protocols can be standardized," says Miller. "You don't want a different system for every anesthetic used in the operating room. You want one that'll do it all."
The researchers also plan to apply their technique to other brain states, including neuropsychiatric disorders like depression and schizophrenia.
"This method is powerful and exciting to apply to different brain states and conditions," says Fiete.
The 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, the Simons Center for the Social Brain, the Simons Collaboration on the Global Brain, the JPB Foundation, the McGovern Institute, and the Picower Institute.
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