Anesthesiologists have a variety of drugs to induce unconsciousness in patients, but exactly how these drugs work has remained a mystery. Now, MIT neuroscientists have unraveled how one 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 delicate balance between stability and excitability. This disruption leads to increasing instability in brain activity until the brain eventually loses consciousness.
“The brain operates on a fine line between being excitable and chaotic. It needs to be excitable enough for neurons to communicate but not so excitable that it becomes chaotic. Propofol disrupts this balance, pushing the brain into instability,” explains Earl K. Miller, Picower Professor of Neuroscience at MIT.
The findings, published in the journal Neuron, could help develop better tools for monitoring patients during general anesthesia.
The research was led by Miller and Ila Fiete, Professor of Brain and Cognitive Sciences at MIT, along with graduate student Adam Eisen and postdoc Leo Kozachkov.
Propofol works by binding to GABA receptors in the brain, inhibiting neurons that possess these receptors. Other anesthesia drugs act on different types of receptors, and how all these drugs induce unconsciousness is not fully understood.
Miller and Fiete hypothesized that propofol, and possibly other anesthetics, interfere with a brain state known as “dynamic stability.” In this state, neurons are excitable enough to respond to new input, but the brain quickly regains control to prevent over-excitability.
Previous studies on anesthesia drugs’ effects on this balance yielded conflicting results: some suggested that anesthesia makes the brain too stable and unresponsive, leading to unconsciousness, while others found the brain becomes too excitable and chaotic. Measuring dynamic stability accurately as consciousness is lost has been challenging.
In their study, the MIT researchers analyzed electrical recordings from the brains of animals given propofol over an hour. The recordings were made in brain areas involved in vision, sound processing, spatial awareness, and executive function.
The researchers used a technique called delay embedding to overcome the limitation of measuring only a small fraction of brain activity. This method allows characterization of dynamic systems from limited measurements by augmenting each measurement with previously recorded data.
Their analysis revealed that in the awake state, neural activity spikes in response to input and then returns to baseline. However, under propofol, the brain took longer to return to baseline, remaining in an overly excited state. This instability increased until the animals lost consciousness.
To confirm their findings, the researchers created a computational model of a neural network. Increasing inhibition in the network, similar to propofol’s effect, led to destabilized activity, mirroring the animal brain observations.
“This paradoxical effect occurs because propofol’s increased inhibitory drive inhibits other inhibitory neurons, leading to an overall increase in brain activity,” explains Fiete.
The researchers believe other anesthetics might also destabilize the brain through different mechanisms. Understanding these common mechanisms could help develop systems to precisely control anesthesia levels, making them safer and more efficient.
Miller and Emery Brown at MIT are working on such systems, which adjust drug dosages in real-time based on brain dynamics.
“If we find common mechanisms across different anesthetics, we can improve safety by adjusting a few parameters instead of developing protocols for each drug individually,” says Miller.
The team also plans to apply their technique to study other brain states, including neuropsychiatric disorders like depression and schizophrenia.
“This method is powerful and exciting. It has the potential to reveal new insights into various brain states and conditions,” Fiete adds.
In summary, MIT scientists have uncovered how propofol induces unconsciousness by disrupting the brain’s balance between stability and excitability, paving the way for better anesthesia control and potentially new treatments for neuropsychiatric disorders.
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The research findings can be found in Neuron.
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