Propofol May Disrupt Brain Stability During Anaesthesia

Propofol and brain stability

The breakdown of controlled inhibition in excessively excited brain cells may help explain the action of propofol, a widely used anaesthetic drug.

A new animal study led by Massachusetts Institute of Technology (MIT) researchers indicates that propofol, a sedative used to safely render patients unconscious during medical procedures, interferes with the brain's usual capacity to bring highly excitable neurons back under control.

"The brain has to operate on this knife's edge between excitability and chaos," explains MIT neuroscientist and senior study author Earl Miller.

"It's got to be excitable enough for its neurons to influence one another, but if it gets too excitable, it spins off into chaos. Propofol seems to disrupt the mechanisms that keep the brain in that narrow operating range."

Measuring propofol anaesthesia in macaques

The researchers monitored brain activity in two rhesus macaques (Macaca mulatta) for an hour while the animals entered unconsciousness after receiving propofol and later regained consciousness.

Hundreds of electrodes positioned on the monkeys' scalps captured electrical signals from four brain regions while the macaques were awake and 'asleep'. The team subsequently assessed those recordings using a newly developed method for measuring the stability, or robustness, of brain activity.

Under normal circumstances, brain activity rises sharply in response to incoming signals before settling again. Once propofol administration started, however, the animals' brain activity needed more time to return to its baseline level. As the anaesthesia deepened, it also grew progressively more excitable, until the animals became unconscious.

The scientists propose that propofol affects inhibitory neurons, which would normally dampen excessive brain activity and restore the system's stability following disruption. With this inhibition lost, instability intensifies until consciousness is lost - as though the system has been thrown off balance and the brain is no longer able to process information.

What scientists know about anaesthetic drugs

This remains only one emerging explanation. Although anaesthetics have been used for almost two centuries, scientists still have only an incomplete understanding of how they function.

A major finding in 1994 indicated that anaesthetics act on proteins involved in cell signalling rather than on the fatty molecules forming cell membranes. Then, in 2018, Australian neuroscientists found that propofol disrupts an important protein used by nerve cells to communicate.

However, as recently as 2020, researchers were still reporting that other widely used anaesthetic drugs interfere with lipid membranes - so it's darn complicated.

By taking a broader view of whole brain networks, scientists have made progress over recent decades in identifying separate neural circuits involved either in anaesthetic-induced unconsciousness or in waking as the drugs' effects wear off.

In a comparable approach, the team behind the new research examined patterns across overall brain activity. They extrapolated from the electrode recordings and used a computer model to test their hypothesis.

Different anaesthetics, possible shared mechanisms

Although the results indicate that propofol inhibits inhibitory neurons, a fruit-fly study published only last month found that another anaesthetic drug may have a broadly opposite effect, acting on excitatory neurons in a different manner.

Instead of releasing excitatory neurons from restraint, isoflurane seems to prevent them from communicating, effectively 'silencing' them.

These contrasting findings could reflect the different drugs investigated: isoflurane is inhaled, whereas propofol is delivered intravenously. They are also known to affect neurons and cell receptors differently.

Nevertheless, the researchers believe anaesthetic drugs may share certain effects on the stability of brain-wide dynamics.

"If you find common mechanisms at work across different anesthetics, you can make them all safer by tweaking a few knobs, instead of having to develop safety protocols for all the different anesthetics one at a time," says Miller.

"You don't want a different system for every anesthetic they're going to use in the operating room. You want one that'll do it all."

The study was published in Neuron.