Propofol, commonly used in general anesthesia, disrupts the normal balance of stability and excitability in the brain.
When it comes to inducing unconsciousness in patients, anesthesiologists have a variety of drugs at their disposal. Understanding how these drugs lead to the loss of consciousness has been a long-standing inquiry. Now, neuroscientists at MIT have provided an answer for one prevalent anesthesia drug.
Through a unique approach to analyzing neuron activity, researchers found that propofol induces unconsciousness by interfering with the brain’s typical equilibrium between stability and excitability. The drug causes brain activity to become progressively less stable until consciousness is lost.
Earl K. Miller, the Picower Professor of Neuroscience at MIT’s Picower Institute for Learning and Memory, explains, “The brain must maintain a delicate balance between excitability and chaos. It needs to be excitable enough for neurons to influence each other, but not too excitable to spiral into chaos. Propofol appears to disrupt the mechanisms that keep the brain in this delicate operational range.”
The new insights, set to be published in Neuron, could aid in the development of improved tools for monitoring patients during general anesthesia.
Professors Earl K. Miller and Ila Fiete, along with MIT graduate student Adam Eisen and postdoc Leo Kozachkov, spearheaded this study.
Journey to Unconsciousness
Propofol acts by binding to GABA receptors in the brain, inhibiting neurons with these receptors. While other anesthesia drugs target different receptor types, the exact mechanism through which all these drugs induce unconsciousness is not completely understood.
Miller, Fiete, and their team theorized that propofol, and potentially other anesthesia drugs, disrupt a brain state known as “dynamic stability.” In this state, neurons exhibit sufficient excitability to respond to new stimuli while the brain swiftly regains control to prevent excessive excitement.
Past studies on how anesthesia drugs affect this balance have yielded conflicting outcomes: some indicating that the brain becomes too stable and unresponsive during anesthesia, leading to unconsciousness, while others suggest the brain becomes overly excitable, resulting in a chaotic state and subsequent unconsciousness.
The challenge lies in accurately measuring dynamic stability in the brain. Monitoring this stability as consciousness diminishes would enable researchers to ascertain if unconsciousness results from too much or too little stability.
In this study, researchers analyzed electrical recordings from different brain regions of animals as they received propofol over an hour, gradually losing consciousness. By utilizing a technique called delay embedding, which augments current measurements with previous ones, researchers could better characterize brain dynamics from limited data.
Upon propofol administration, the brain took longer to return to its normal state after stimuli, staying in an overly excited state. This heightened state intensified until the animals entered unconsciousness, indicating that propofol’s inhibition of neuron activity leads to increasing instability and subsequent unconsciousness.
Enhancing Anesthesia Management
To validate this effect in a computational model, researchers created a basic neural network. Elevating inhibition in certain nodes, mimicking propofol’s action in the brain, led to network destabilization, resembling the unstable activity observed in animals receiving propofol.
Adam Eisen elaborated, “When we adjusted inhibition in a simple neural network, we observed destabilization. Therefore, we suggest that increased inhibition can induce instability, eventually causing loss of consciousness.”
As Fiete clarified, “This counterintuitive outcome due to enhanced inhibition destabilizing the network instead of quieting or stabilizing it is attributed to disinhibition. Propofol’s increase in inhibitory drive inhibits other inhibitory neurons, resulting in heightened brain activity.”
The researchers suspect that other anesthesia drugs affecting diverse neuron types and receptors may lead to a similar outcome through different routes, a possibility they are exploring further.
If substantiated, this could streamline efforts towards more precise anesthesia control systems. These systems, developed in collaboration with Emery Brown, aim to gauge brain dynamics and adjust drug dosages in real-time.
Earl K. Miller emphasized, “By identifying common mechanisms across various anesthetics, we can enhance their safety by making minor adjustments rather than developing safety protocols individually for each one. A universal system for all anesthetics in the operating room would be more efficient.”
Further, the researchers plan to apply their dynamic stability measurement technique to various brain states, including neuropsychiatric disorders.
Ila Fiete expressed, “This approach holds promise, and we look forward to extending it to different brain states, anesthesia types, and various neuropsychiatric conditions like depression and schizophrenia.”
