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Anesthesia blocks sensation by cutting off communication within the cortex

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Anesthesia blocks sensation by cutting off communication within the cortex


General anesthesia evokes a dual mystery: How does it disrupt consciousness, including sensory perception, and what might that say about the nature of consciousness. A new study led by researchers at The Picower Institute for Learning and Memory at MIT provides evidence in animals that consciousness depends on properly synchronized communication across the brain’s cortex and that the anesthetic drug propofol cancels sensory processing by cutting it off.

In the Journal of Cognitive Neuroscience, researchers report clear evidence that in anesthetized animals, sounds and tactile sensations still produced neural activity in an area of the cortex that receives incoming sensory information. But just as clearly, measurements of neural spiking and broader oscillatory activity showed that those signals failed to propagate to three other cortical regions with higher-level processing and cognitive responsibilities, as seen during normal wakefulness.

“What this study shows is that the cortex isn’t getting on the same page,” said study corresponding author Earl K. Miller, Picower Professor in the Department of Brain and Cognitive Sciences at MIT. “Information is making it to the cortex. It’s being registered in primary sensory areas. It’s just not reaching the rest of the cortex. Because of the anesthesia, it only makes it part of the way through.”

The significance of that, said co-senior author Emery N. Brown, Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience, is that “the study suggests that consciousness requires coordination of activities among cortical regions. Simply activating one or more of these regions is not sufficient.”

Study lead author John Tauber, who recently earned his Ph.D. at MIT in Brown’s lab, said the study could aid efforts to improve anesthesiology care. Brown is an anesthesiologist at Massachusetts General Hospital as well as an MIT professor of Brain and Cognitive Sciences, a member of the Institute for Medical Engineering and Science, and a faculty member of Harvard Medical School.

“We hope our paper further highlights the importance of actively monitoring what is happening in the brain during anesthesia,” Tauber said. “Future studies in this direction will help us develop clear indicators of whether a patient is still processing sensory information. This would allow anesthesiologists to adjust drug dosage and prevent intraoperative awareness from occurring.”

Stymied sensory processing

To conduct the study the team worked with two animal subjects to measure brain activity — both the electrical “spiking” of individual neurons and their collective rhythmic activity — via electrode arrays placed in four areas of the cortex both before and after they underwent propofol general anesthesia. The researchers selected the areas of the cortex to represent its hierarchical continuum of functions from initial sensation (the superior temporal gyrus, or STG) to increasingly high levels of cognition (the posterior parietal cortex, or PPC; Region 8A; and the prefrontal cortex, or PFC).


During both states of consciousness, the animals experienced specific stimulations: two audio tones, including one on its own and another paired with a puff of air on the face. In the awake state, such stimulation produced an increase all cortical areas in alpha/beta frequency activity. STG also showed a strong increase in higher frequency oscillations. The response changed dramatically under anesthesia. While the alpha and beta frequency response was diminished in STG, it virtually vanished in all the higher cortical regions.

“We expected to see a more gradual loss of responses and information,” Tauber said. “The drop-off in responses during anesthesia from auditory cortex (STG) to associative cortex (PPC) was striking.”

Along with the decrease in activity, the researchers measured a decrease in the sensory information detectable in the brain as they moved up the cortical hierarchy. “Decoder” software found sensory information in all areas of the cortex during the awake state but during unconsciousness, less and less information could be found the higher up the cortex the researchers looked.

An incoherent cortex

When the researchers next measured the synchronization of activity among brain regions, they found that it, too, broke down under anesthesia. When animals were awake, they exhibited a strong degree of synchronization in alpha/beta oscillation activity but when unconscious, “there was little or no stimulus-induced synchronization for any of the pairs of cortical areas,” the researchers reported.

A feature of the propofol-anesthetized brain is that neural oscillation activity takes on distinct “up” and “down” states of greater or lesser activity over time. To test whether sensory information is cut off during both states or just the down states, the researchers developed a statistical analysis. They found that while all neuronal spiking was indeed low during the down states, even during up states when sensory signals were measurable in STG they still failed to go beyond that region.


“We expected responses in the higher cortical areas to at least be disrupted during up states, but it was a bit surprising to find the responses disappeared almost entirely,” Tauber said. “The neural activity during up states is functionally quite different from the awake state, but we think we have just scratched the surface in understanding the differences between the two.”

In sum, the evidence in the new study shows that unconsciousness doesn’t arise from a wholesale shutting down of the cortex, as much as a suppression of communication within it, Miller said.

A key next question to answer is how propofol enforces that suppression.

“What is it about these changing dynamics that blocks the flow of information through cortex?” Miller asks. “What’s the headwind that’s blowing back that sensory information and keeping it in the sensory cortex?”

Tauber added that the team looked at sensory processing only when they were certain the animals were fully unconscious. It could be informative, he said, to study how sensory processing changes during the transition from wakefulness to that fully unconscious state.

In addition to Tauber, Miller and Brown, the paper’s other authors are Scott Brincat, Emily Stephen, Jacob Donoghue and Leo Kozachkov.

The National Institutes of Health, The Office of Naval Research, The JPB Foundation and The Picower Institute for Learning and Memory funded the research.



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Simple test for flu could improve diagnosis and surveillance

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Simple test for flu could improve diagnosis and surveillance


Fewer than one percent of people who get the flu every year get tested, in part because most tests require trained personnel and expensive equipment. Now researchers have developed a low-cost paper strip test that could allow more patients to find out which type of flu they have and get the right treatment.

The test, developed by a team from the Broad Institute of MIT and Harvard and Princeton University, and supported by the US Centers for Disease Control and Prevention, uses CRISPR to distinguish between the two main types of seasonal flu, influenza A and B, as well as seasonal flu subtypes H1N1 and H3N2. It can also identify strains that resist antiviral treatment, and with further work, could potentially detect swine and avian flu strains, including H5N1, which is currently infecting cattle.

Appearing in The Journal of Molecular Diagnostics, the results could help improve outbreak response and clinical care by bringing tests that are accurate, low-cost, and fast to doctors’ offices and labs across the US and in other countries.

“Ultimately, we hope these tests will be as simple as rapid antigen tests, and they’ll still have the specificity and performance of a nucleic acid test that would normally be done in a laboratory setting,” said Cameron Myhrvold, co-senior author on the study along with Pardis Sabeti, an institute member at the Broad and a professor at Harvard University and the Harvard T.H. Chan School of Public Health, as well as a Howard Hughes Medical Institute investigator. Myhrvold, who is currently an assistant professor at Princeton University, was a postdoctoral researcher in Sabeti’s lab when the study began.

SHINE a light

The test is based on a technology called SHINE, which was developed by Sabeti’s lab in 2020 and uses CRISPR enzymes to identify specific sequences of viral RNA in samples. The researchers first used SHINE to test for SARS-CoV-2, and later to distinguish between the Delta and Omicron variants. Then, in 2022, they began adapting the assay to detect other viruses they knew were always circulating: influenzas. They wanted to create tests that could be used in the field or in clinics rather than hospitals or diagnostic labs with expensive equipment.

“Using a paper strip readout instead of expensive fluorescence machinery is a big advancement, not only in terms of clinical care but also for epidemiological surveillance purposes,” said Ben Zhang, co-first author on the study, a medical student at Harvard Medical School and an undergraduate researcher in Sabeti’s lab when the study began.

Typical diagnostic approaches such as polymerase chain reaction (PCR) require lengthy processing times, trained personnel, specialized equipment, and freezers to store reagents at -80°C, whereas SHINE can be conducted at room temperature in about 90 minutes. Currently, the assay only requires an inexpensive heat block to warm the reaction, and the researchers are working to streamline the process with the goal of returning results in 15 minutes.

The researchers also adapted SHINE to distinguish between different flu strains. In the future, they say the assay could be adapted to detect two different viruses with similar symptoms, such as influenza and SARS-CoV-2.

“Being able to tease apart what strain or subtype of influenza is infecting a patient has repercussions both for treating them and public health interventions,” said Jon Arizti-Sanz, a postdoctoral researcher in Sabeti’s lab and co-first author on the study.

For example, the tests could help clinicians decide whether to use Oseltamivir, a common antiviral that is effective for only some strains, Arizti-Sanz added. In the field, rapid testing could also help scientists collect samples more strategically during an outbreak to better monitor how the virus is spreading.

Next, the researchers are adapting SHINE to test for both avian and swine influenza strains. “With SARS-CoV-2 and now flu, we’ve shown that we can easily adapt SHINE to detect new or evolving viruses,” Arizti-Sanz said. “We’re excited to apply it to H5N1.”



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Prying open the AI black box

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Prying open the AI black box


Artificial intelligence continues to squirm its way into many aspects of our lives. But what about biology, the study of life itself? AI can sift through hundreds of thousands of genome data points to identify potential new therapeutic targets. While these genomic insights may appear helpful, scientists aren’t sure how today’s AI models come to their conclusions in the first place. Now, a new system named SQUID arrives on the scene armed to pry open AI’s black box of murky internal logic.

SQUID, short for Surrogate Quantitative Interpretability for Deepnets, is a computational tool created by Cold Spring Harbor Laboratory (CSHL) scientists. It’s designed to help interpret how AI models analyze the genome. Compared with other analysis tools, SQUID is more consistent, reduces background noise, and can lead to more accurate predictions about the effects of genetic mutations.

How does it work so much better? The key, CSHL Assistant Professor Peter Koo says, lies in SQUID’s specialized training.

“The tools that people use to try to understand these models have been largely coming from other fields like computer vision or natural language processing. While they can be useful, they’re not optimal for genomics. What we did with SQUID was leverage decades of quantitative genetics knowledge to help us understand what these deep neural networks are learning,” explains Koo.

SQUID works by first generating a library of over 100,000 variant DNA sequences. It then analyzes the library of mutations and their effects using a program called MAVE-NN (Multiplex Assays of Variant Effects Neural Network). This tool allows scientists to perform thousands of virtual experiments simultaneously. In effect, they can “fish out” the algorithms behind a given AI’s most accurate predictions. Their computational “catch” could set the stage for experiments that are more grounded in reality.

“In silico [virtual] experiments are no replacement for actual laboratory experiments. Nevertheless, they can be very informative. They can help scientists form hypotheses for how a particular region of the genome works or how a mutation might have a clinically relevant effect,” explains CSHL Associate Professor Justin Kinney, a co-author of the study.

There are tons of AI models in the sea. More enter the waters each day. Koo, Kinney, and colleagues hope that SQUID will help scientists grab hold of those that best meet their specialized needs.

Though mapped, the human genome remains an incredibly challenging terrain. SQUID could help biologists navigate the field more effectively, bringing them closer to their findings’ true medical implications.



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Iron meteorites hint that our infant solar system was more doughnut than dartboard

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Iron meteorites hint that our infant solar system was more doughnut than dartboard


Four and a half billion years ago, our solar system was a cloud of gas and dust swirling around the sun, until gas began to condense and accrete along with dust to form asteroids and planets. What did this cosmic nursery, known as a protoplanetary disk, look like, and how was it structured? Astronomers can use telescopes to “see” protoplanetary disks far away from our much more mature solar system, but it is impossible to observe what ours might have looked like in its infancy — only an alien billions of light years away would be able to see it as it once was.

Fortunately, space has dropped a few clues — fragments of objects that formed early in solar system history and plunged through Earth’s atmosphere, called meteorites. The composition of meteorites tells stories of the solar system’s birth, but these stories often raise more questions than answers.

In a paper published in Proceedings of the National Academy of Sciences, a team of planetary scientists from UCLA and Johns Hopkins University Applied Physics Laboratory reports that refractory metals, which condense at high temperatures, such as iridium and platinum, were more abundant in meteorites formed in the outer disk, which was cold and far away from the sun. These metals should have formed close to the sun, where the temperature was much higher. Was there a pathway that moved these metals from the inner disk to the outer?

Most meteorites formed within the first few million years of solar system history. Some meteorites, called chondrites, are unmelted conglomerations of grains and dust left over from planet formation. Other meteorites experienced enough heat to melt while their parent asteroids were forming. When these asteroids melted, the silicate part and the metallic part separated due to their difference in density, similar to how water and oil don’t mix.

Today, most asteroids are located in a thick belt between Mars and Jupiter. Scientists think that Jupiter’s gravity disrupted the course of these asteroids, causing many of them to smash into each other and break apart. When pieces of these asteroids fall to Earth and are recovered, they are called meteorites.

Iron meteorites are from the metallic cores of the earliest asteroids, older than any other rocks or celestial objects in our solar system. The irons contain molybdenum isotopes that point toward many different locations across the protoplanetary disk in which these meteorites formed. That allows scientists to learn what the chemical composition of the disk was like in its infancy.

Previous research using the Atacama Large Millimeter/submillimeter Array in Chile has found many disks around other stars that resemble concentric rings, like a dartboard. The rings of these planetary disks, such as HL Tau, are separated by physical gaps, so this kind of disk could not provide a route to transport these refractory metals from the inner disk to the outer.

The new paper holds that our solar disk likely didn’t have a ring structure at the very beginning. Instead, our planetary disk looked more like a doughnut, and asteroids with metal grains rich in iridium and platinum metals migrated to the outer disk as it rapidly expanded.

But that confronted the researchers with another puzzle. After the disk expansion, gravity should have pulled these metals back into the sun. But that did not happen.

“Once Jupiter formed, it very likely opened a physical gap that trapped the iridium and platinum metals in the outer disk and prevented them from falling into the sun,” said first author Bidong Zhang, a UCLA planetary scientist. “These metals were later incorporated into asteroids that formed in the outer disk. This explains why meteorites formed in the outer disk — carbonaceous chondrites and carbonaceous-type iron meteorites — have much higher iridium and platinum contents than their inner-disk peers.”

Zhang and his collaborators previously used iron meteorites to reconstruct how water was distributed in the protoplanetary disk.

“Iron meteorites are hidden gems. The more we learn about iron meteorites, the more they unravel the mystery of our solar system’s birth,” Zhang said.



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