Ultrasound Puts Animals into a Curious Hibernation-Like State

In some species, when the going gets tough, the body hits the brakes, chilling body temperature and slowing metabolism to a snail’s pace in a state known as torpor. Humans do not enter torpor, but the condition might offer benefits across scenarios as seemingly unrelated as intensive care unit (ICU) stays and long-distance space travel.

Using therapeutic ultrasound waves targeted at a deep region of the brain, researchers at Washington University in St. Louis and the University of Washington induced a torporlike state in mice without physically invading their skull. Mice can naturally enter this suspended state, so the scientists also tested the technique in rats, animals in which torpor is not part of their repertoire. The findings, published on May 25 in Nature Metabolism, could potentially inform research on targeting different brain areas with ultrasound to regulate other bodily activities.

The approach is noninvasive, which is “terrific for many applications,” says Matteo Cerri, an associate professor at the department of biomedical and neuromotor sciences at the University of Bologna in Italy, who was not involved in the work. It seems to be flexible enough to act as a “thermostat, conceptually,” allowing for adjustments of the ultrasound stimulus as needed to change temperature, he says.

Using a noninvasive technique is an important step in advancing torpor induction toward human use, says clinician Michael Ambler, a researcher and lecturer studying torpor at the School of Physiology, Pharmacology & Neuroscience at the University of Bristol in England, who was not involved in the work.

Some earlier efforts relied on injecting a gene for a protein into the targeted region to assist in activating cells under stimulation with light or drugs. Such invasive approaches are unlikely to gain approval for human use, Ambler says, making the new study “an extremely interesting piece of work.”

To trigger a torporlike state noninvasively, researchers placed a tiny helmetlike probe on their rodent subjects that stimulated a deep brain structure with ultrasound waves. The team chose ultrasound frequencies that are different from those used for medical purposes, such as prenatal screening. The target region was the preoptic area of the hypothalamus, which contains neurons that previous work suggests play a role in torpor.

Stimulating these neurons prods them to send signals to brown adipose tissue, a highly metabolic fat located on the upper back that is tasked with turning up body heat when things get too chilled. The ultrasound-triggered messages from the preoptic area inhibited activity in the mice’s brown fat, preventing it from elevating the heat. To confirm the chill, researchers used an infrared camera to track skin cooling over the brown fat area and heat loss in the animals’ tail. They also confirmed the rodents’ slowed metabolism by measuring the declines in their oxygen use. Along with the chilled fat and sluggish metabolism, the mice showed other signs of being in a torporlike state, such as reduced movement and a decreased heart rate.

Mice can enter into a natural torpor when frightened or stressed. To ensure that the ultrasound, not stress or fear, was triggering the temperature drop, the investigators turned to rats, which lack this natural response. The ultrasound signal also induced a colder body temperature in the rats, suggesting that ultrasound waves to the preoptic area were the cause of the torporlike state.

The effect in rats was mild, says Hong Chen, an associate professor at the department of biomedical engineering and radiation oncology at Washington University in St. Louis and senior author of the study. “The rat study was just proof of concept” that the stimulus would work in nontorporous animals, she says, adding that the research still has “a long way to go.”

The investigators automated the stimulus process to keep the animals in a torporlike state. An uptick in temperature triggered the ultrasound stimulus, cooling things out again, much like a thermostat. Mice were kept in this state for 24 hours during the experiment, and when the ultrasound stimulation was switched off, normal temperature and metabolism was rapidly restored with no apparent negative aftermath.

A deeper look at what the cells were doing in response to the stimulus showed that the ultrasound waves affected the flow of ions such as calcium into the pre-optic neurons, triggering signals that reach the brown fat and keep it from warming things up. When investigators removed the protein responsible for controlling this flow, ultrasound had less effect on reducing body temperature.

These results imply that the protein is “like a nanoswitch,” Chen says. She views this finding as the most important of the study because similar proteins in other brain regions also may be sensitive to the ultrasound stimulus. “If we can identify ultrasound-sensitive [proteins] in other parts of the brain, we may modulate other behaviors,” she says, adding that what those might be remains to be seen.

The potential to alter behavior by bombarding the brain with ultrasound may have ethical implications. “In tech, we have to think about whether there’s a dark side or not,” Chen says. “I think the chance will be low because for this tech to work, we need well-designed devices that can precisely target a specific brain region, which is extremely challenging to do.”

The technology will have to overcome initial skepticism. “As it stands, I think you can’t really send someone into some degree of hypothermia” with a technique such as this, says Cerri, noting that there are other, far easier ways to render a person unconscious.

If noninvasive induction of torpor were to become possible in humans, one potential use would be to buy stroke or heart attack patients time in transport to the hospital, Chen says. Both of these emergencies result in oxygen deprivation to affected tissues, and because torpor involves a lower oxygen demand, the damage could be delayed or prevented.

In the ICU, torpor induction could preclude the need for the many drugs and monitoring involved in patient care. Ambler, who studies torpor as a way to support patients in the ICU who are undergoing organ failure, says, “This study presents a very first step toward that goal.”

Torpor induction in humans also holds the futuristic potential to support suspended animation for journeys across vast stretches of lonely space.

Before that possibility takes flight in some aspirational future, research on a familiar earthbound species must come first. Cerri says the next step should be testing in larger, nonhuman animals, probably pigs. “They are most like humans—hairless and thermally similar to humans,” he says.

Chen agrees that pigs probably are the next rung on the ladder to payoffs in torpor induction. “We want to push the technique step by step, from mice to rats to pigs to monkeys and then, hopefully, eventually to humans”—and then, perhaps, beyond the bounds of planet Earth.

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