Summary: Neuroscientists have discovered that the anesthetic propofol causes unconsciousness by disrupting the balance between stability and excitability in the brain. The drug causes brain activity to become increasingly unstable, preventing the brain from maintaining normal consciousness.
This discovery could contribute to the development of better tools for monitoring and controlling anesthesia during surgery. The results highlight the potential for improving the safety and effectiveness of anesthetics.
Highlights:
- Mechanism revealed: Propofol disrupts brain stability, causing loss of consciousness.
- New technique: The researchers used a new method to analyze neuron activity and brain dynamics.
- Future applications: This knowledge could lead to better control of anesthesia and safer surgical procedures.
Source: WITH
Anesthesiologists can use many drugs to induce unconsciousness in patients. Exactly how these drugs cause the brain to lose consciousness has long been a question, but now MIT neuroscientists have answered that question for a commonly used anesthetic drug.
Using a new technique for analyzing neural activity, researchers have discovered that the drug propofol causes unconsciousness by disrupting the brain’s normal balance between stability and excitability. The drug makes brain activity increasingly unstable, until the brain loses consciousness.
“The brain must operate on a fine line between excitability and chaos. It must be excitable enough for its neurons to influence each other, but if it becomes too excitable, it descends into chaos.
“Propofol appears to disrupt the mechanisms that keep the brain in this narrow operating range,” says Earl K. Miller, Picower Professor of Neuroscience and a member of MIT’s Picower Institute for Learning and Memory.
The new findings, which will appear in Neuroncould help researchers develop better tools to monitor patients while they undergo general anesthesia.
Miller and Ila Fiete, professor of brain and cognitive sciences, director of the K. Lisa Yang Integrative Computational Neuroscience Center (ICoN), and a member of MIT’s McGovern Institute for Brain Research, are the lead authors of the new study. MIT graduate student Adam Eisen and MIT postdoctoral fellow Leo Kozachkov are the study’s senior authors.
Loss of consciousness
Propofol is a drug that binds to GABA receptors in the brain, thereby inhibiting neurons that have these receptors. Other anesthetic drugs act on different types of receptors, and the mechanism by which all of these drugs cause loss of consciousness is not fully understood.
Miller, Fiete and their students hypothesized that propofol, and perhaps other anesthetics, interfere with a brain state known as “dynamic stability.” In this state, neurons have enough excitability to respond to new information, but the brain is able to quickly regain control and prevent them from becoming overexcited.
Previous studies on how anesthetic drugs affect this balance have produced conflicting results: some have suggested that during anesthesia, the brain becomes too stable and unresponsive, leading to loss of consciousness. Others have found that the brain becomes too excitable, leading to a chaotic state that ultimately leads to loss of consciousness.
These conflicting results are partly explained by the difficulty of accurately measuring the brain’s dynamic stability. Measuring dynamic stability during loss of consciousness would help researchers determine whether unconsciousness results from too much or too little stability.
In this study, the researchers analyzed electrical recordings made in the brains of animals given propofol for one hour, during which they gradually lost consciousness. The recordings were made in four areas of the brain involved in vision, sound processing, spatial perception and executive function.
These recordings covered only a tiny fraction of the brain’s overall activity. To address this, the researchers used a technique called delay embedding. This technique allows researchers to characterize dynamic systems from limited measurements by augmenting each measurement with previously recorded measurements.
Using this method, the researchers were able to quantify how the brain responds to sensory inputs, such as sounds, or to spontaneous disturbances in neural activity.
In a normal state of wakefulness, neuronal activity increases after each stimulation and then returns to its baseline level of activity. However, once propofol dosing began, the brain began to take longer to return to its baseline level after these stimulations, remaining in a state of excessive excitement. This effect became increasingly pronounced until the animals lost consciousness.
This suggests that propofol’s inhibition of neuronal activity leads to increasing instability, which causes the brain to lose consciousness, the researchers say.
Better control of anesthesia
To see if they could reproduce this effect in a computer 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, the network’s activity became destabilized, similar to the unstable activity the researchers observed in the brains of animals given propofol.
“We studied a simple circuit model of interconnected neurons, and when we found inhibition, we observed destabilization. So we suggest that increased inhibition can generate instability, which is then linked to loss of consciousness,” Eisen says.
As Fiete explains, “This paradoxical effect, in which increased inhibition destabilizes the network instead of silencing or stabilizing it, occurs because of disinhibition. When propofol increases the inhibitory drive, that drive inhibits other inhibitory neurons, leading to an overall increase in brain activity.”
The researchers suspect that other anesthetic drugs, which act on different types of neurons and receptors, might converge on the same effect through different mechanisms – a possibility they are currently exploring.
If true, it could help researchers 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 brain dynamics and then adjusting drug dosages accordingly, in real time.
“If you find common mechanisms across different anesthetics, you can make them all safer by changing a few buttons, instead of having to develop safety protocols for all the different anesthetics one by one,” Miller says. “You don’t want a different system for every anesthetic that’s used in the operating room. You want one system that can do everything.”
The researchers also plan to apply their technique of measuring dynamic stability to other brain states, including neuropsychiatric disorders.
“This method is quite powerful, and I think it will be very interesting to apply it to different brain states, to different types of anesthesia, as well as to other neuropsychiatric disorders like depression and schizophrenia,” Fiete says.
Funding: 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’s Computer and Information Sciences and Engineering Directorate, the Simons Center for the Social Brain, the Simons Collaboration on the Global Brain, the JPB Foundation, the McGovern Institute, and the Picower Institute.
About this news on consciousness and anesthesia research
Author: Abby Abazorius
Source: WITH
Contact: Abby Abazorius – MIT
Picture: Image credited to Neuroscience News
Original research: The results will appear in Neuron