How the brain loses consciousness under general anesthesia has long been a puzzle in neuroscience. Three of the most commonly used drugs—propofol, ketamine, and dexmedetomidine—act on entirely different molecular targets, yet all reliably induce unconsciousness. A new study from MIT titled “Similar destabilization of neural dynamics under different general anesthetics” now shows that despite their divergent mechanisms, these drugs produce a shared pattern of neural destabilization in the brain. The findings, published in Cell Reports, suggest a common mechanism underlying anesthesia‑induced loss of consciousness.
In the awake brain, neural circuits operate within a narrow window of stability and excitability. Too little excitability and information cannot propagate; too much and activity becomes chaotic. “The nervous system has to operate on a knife’s edge in this narrow range of excitability,” said Earl Miller, PhD, the Picower professor of neuroscience and a member of MIT’s Picower Institute for Learning and Memory, in a press release. “It has to be excitable enough so different parts can influence one another, but if it gets too excited, it goes off into chaotic activity.”
In 2024, Miller’s group showed that propofol disrupts this balance, pushing neural activity toward increasing instability as the drug dose rises. In the new study, the team asked whether this destabilization is unique to propofol or reflects a broader principle of anesthesia.
To answer that, the researchers developed a computational model capable of quantifying how neural activity responds to external inputs and how long it takes to return to baseline—a measure of the brain’s stability. They applied this framework to neural recordings from animals receiving one of the three anesthetics. The dataset included spontaneous activity as well as responses to auditory tones, allowing the team to track how the drugs altered both ongoing dynamics and stimulus‑evoked patterns.
The result was striking: all three anesthetics produced the same signature of destabilization, even though they act on different receptor systems. Propofol enhances GABAergic inhibition, dexmedetomidine suppresses norepinephrine release, and ketamine blocks NMDA receptors. Yet the model could not distinguish which drug was being administered based on the destabilization metric alone.
“All three of these drugs appear to do the exact same thing,” Miller said. “In fact, you could look at the destabilization measure we use, and you can’t tell which drug is being applied.”
Lead author Adam Eisen, a graduate student in Miller’s lab, noted that the convergence is especially intriguing given the mechanistic diversity. “The molecular mechanisms of ketamine and dexmedetomidine are a bit more involved than propofol,” he said. “A future direction is to do a meaningful model of what the biophysical effects of those are and see how that could lead to destabilization.”
The work also points toward practical applications. A universal neural signature of unconsciousness could support the development of standardized anesthesia‑delivery systems that monitor brain stability directly rather than relying on indirect physiological markers. Miller and collaborator Emery Brown, MD, PhD, the Edward Hood Taplin professor of medical engineering and computational neuroscience, are now working on an automated control system that uses EEG to track neural stability and adjust drug dosing in real time. Such a system could help ensure patients remain unconscious without drifting into excessively deep anesthesia, which is associated with postoperative complications in some patients.
“What’s exciting is the possibility of a universal anesthesia‑delivery system that can measure this one signal and tell how unconscious you are, regardless of which drugs they’re using in the operating room,” Miller said.
