There are many drugs that anesthesiologists can use to induce unconsciousness in patients, but exactly how these drugs cause the brain to lose consciousness has been a longstanding question. A study in non-human primates by MIT neuroscientists has now answered that question for one commonly used anesthesia drug, propofol.
Using a novel technique known as DeLASE (delayed linear analysis for stability estimation) to analyze neuronal activity, the researchers’ study in macaques discovered that propofol induces unconsciousness by disrupting the brain’s normal balance between stability and excitability. The findings indicated that the drug causes brain activity to become increasingly unstable, until the brain loses consciousness.
The new findings could help researchers develop better tools for monitoring patients as they undergo general anesthesia. “The brain has to operate on this knife’s edge between excitability and chaos,” said Earl K. Miller, PhD, the Picower Professor of Neuroscience and a member of MIT’s Picower Institute for Learning and Memory. “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.”
The team further indicated the potential to apply their method for tracking changes in the stability of neural dynamics as part of monitoring treatment for psychiatric and mood disorders. Miller, and Ila Fiete, PhD, a professor of brain and cognitive sciences, the director of the K. Lisa Yang Integrative Computational Neuroscience Center (ICoN), and a member of MIT’s McGovern Institute for Brain Research, are senior authors of the team’s report on their anesthesia-related study, published in Neuron. In their paper, titled “Propofol anesthesia destabilizes neural dynamics across cortex,” the researchers concluded “Overall, our analysis suggests a mechanism for anesthesia that involves destabilizing brain activity to the point where the brain loses the ability to maintain conscious awareness.” Lead authors on the report are MIT graduate student Adam Eisen and MIT postdoc Leo Kozachkov, PhD.
Every day, hundreds of thousands of people undergo general anesthesia, the authors wrote. Propofol binds to GABA receptors in the brain, inhibiting neurons that have those receptors. Other anesthesia drugs act on different types of receptors. But while the pharmacological action and neurophysiological response of propofol, are well recognized, the mechanism by which propofol and other anesthetics render unconsciousness are not well understood. Miller, Fiete, and colleagues hypothesized that propofol, and possibly other anesthesia drugs, interfere with a brain state known as dynamic stability. “One hypothesis is that anesthesia disrupts dynamic stability—the ability of the brain to balance excitability with the need to be stable and controllable,” the team commented.
In this state, neurons have enough excitability to respond to new input, but the brain is able to quickly regain control and prevent them from becoming overly excited. “Brain states should be sufficiently excitable for generation of widespread activity and information integration. But they also need to be controllable and stable, reliably producing the same computations,” the investigators further noted.
Prior studies on how anesthesia drugs affect this balance have reported conflicting results. Some suggested that during anesthesia the brain shifts toward becoming too stable and unresponsive, which leads to loss of consciousness. Others found that the brain becomes too excitable, leading to a chaotic state that results in unconsciousness. “Previous work on cortical stability during anesthesia has produced contradictory results, suggesting that anesthesia either destabilizes or excessively stabilizes neural dynamics,” the authors noted.
Part of the reason for these conflicting results is that it has been difficult to accurately measure dynamic stability in the brain. “This could be due to a paucity of studies using high-density intracortical electrophysiology and the inability to therefore apply sufficiently rich dynamical tools to assess stability,” the team continued.
Measuring dynamic stability as consciousness is lost would help researchers determine if unconsciousness results from too much stability or too little stability. For their newly reported study the researchers analyzed electrical recordings made in the brains of animals that received propofol over an hour-long period, during which they gradually lost consciousness. The recordings were made in four areas of the brain that are involved in vision, sound processing, spatial awareness, and executive function. “… we used a dataset of local field potential (LFP) recordings with hundreds of electrodes from multiple brain regions in two non-human primates (NHPs, specifically adult rhesus macaque monkeys) as they lost and regained consciousness due to propofol anesthesia … “Electrodes were placed in four areas: ventrolateral prefrontal cortex, frontal eye fields, posterior parietal cortex, and auditory cortex.”
These recordings covered only a tiny fraction of the brain’s overall activity, so to overcome that the researchers used a technique called delay embedding. This technique allows researchers to characterize dynamical systems from limited measurements by augmenting each measurement with measurements that were recorded previously. “We introduce a new approach—delayed linear analysis for stability estimation (DeLASE). DeLASE directly quantifies changes in stability in neural data,” they explained.
The researchers were able to validate their method, and applied the technology to quantify how the brain responds to sensory inputs, such as sounds, or to spontaneous perturbations of neural activity. They then used their method to determine the impact of propofol anesthesia on the stability of neural dynamics by analyzing multi-electrode activity recorded in two non-human primates. They found that in the normal, awake state, neural activity spikes after any input, then returns to its baseline activity level. However, once propofol dosing began, the brain started taking longer to return to its baseline after these inputs, remaining in an overly excited state. This effect became more and more pronounced until the animals lost consciousness. The results, the team suggested, indicate that propofol’s inhibition of neuron activity leads to escalating instability, which causes the brain to lose consciousness.
To see if they could replicate this effect in a computational 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, network activity became destabilized, similar to the unstable activity the researchers saw in the brains of animals that received propofol.
“We looked at a simple circuit model of interconnected neurons, and when we turned up inhibition in that, we saw a destabilization, “Eisen said. “So, one of the things we’re suggesting is that an increase in inhibition can generate instability, and that is subsequently tied to loss of consciousness.”
As Fiete explained, “This paradoxical effect, in which boosting inhibition destabilizes the network rather than silencing or stabilizing it, occurs because of disinhibition. When propofol boosts the inhibitory drive, this drive inhibits other inhibitory neurons, and the result is an overall increase in brain activity.”
The researchers suspect that other anesthetic drugs, which act on different types of neurons and receptors, may converge on the same effect through different mechanisms — a possibility that they are now exploring.
If this turns out to be true, it could be helpful to the researchers’ ongoing efforts to develop ways to more precisely control the level of anesthesia that a patient is experiencing. These systems, which Miller is working on with Emery Brown, PhD, the Edward Hood Taplin Professor of Medical Engineering at MIT, work by measuring the brain’s dynamics and then adjusting drug dosages accordingly, in real-time.
“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,” Miller says. “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 researchers also plan to apply their technique for measuring dynamic stability to other brain states, including neuropsychiatric disorders. The hypothesized deep connection between neural stability and psychiatric disorders suggests that measuring changes in stability could be an excellent approach for monitoring treatment efficacy, they stated. “Conditions such as depression, anxiety, substance use disorder, and schizophrenia can all be characterized as having distorted thinking patterns relative to neurotypical states, distortions that have been hypothesized to arise from changes to the stability landscape … Tracking changes in stability in neural dynamics over time for individuals with these conditions could help shape the course of treatment.” It could also help to shed light on the mechanisms of interventions like psychedelics and meditation, which are thought to disrupt overly stable dynamics, the scientists pointed out.
“This method is pretty powerful, and I think it’s going to be very exciting to apply it to different brain states, different types of anesthetics, and also other neuropsychiatric conditions like depression and schizophrenia,” Fiete added.
