Researchers restored the respiration of rats undergoing opioid overdoses by sending a pair of high-frequency signals into their spinal cords, triggering neurons responsible for breathing with a recently invented approach to manipulating brain cells.
Described in a paper published in Nature last week, the deep-brain stimulation technique could one day be used to save lives if proved to be safe and effective in humans. The researchers said their new method could be more easily applicable than other overdose treatments.
At toxic doses, opioids such as morphine, heroin and fentanyl can cause users to lose consciousness and mostly or fully stop breathing through neuron disruption, which can lead to death if not rapidly treated. In the U.S., nearly 50,000 people died from overdoses involving opioids in 2019, according to the Centers for Disease Control and Prevention. The country’s annual count has been rising for decades, driven most recently by a surge in the use of fentanyl and other synthetic opioids.
During opioid overdoses, breathing is most commonly restored using naloxone, a medication that rapidly counteracts the painkillers’ effects. Mouth-to-mouth rescue breathing and chest compressions can also be used to temporarily sustain respiration.
Led by University of Florida researchers, the new study takes inspiration from 2017 research led by Massachusetts Institute of Technology scientists, who were the first to use two energy waves to stimulate neurons in the brain. Small differences between their frequencies cause periodic spikes in energy at their intersection that made the targeted neurons fire. The individual frequencies were too high to interfere with neuron function, so the waves did not trigger any other cells they passed through.
Known as temporal-interference stimulation, the method for activating neurons used electrodes placed on the scalp, an improvement upon other approaches that required surgically implanting electrodes in the brain.
“This is a very unique way of stimulating neurons where you direct energy from two different sources; you essentially make it collide deep within the tissue,” said David Fuller, a professor of physical therapy at the University of Florida and the study’s senior author. “What we thought is, maybe this could also work to activate the spinal cord, because that's where the motor neurons that control the diaphragm reside.”
Led by former Florida Ph.D. student Michael Sunshine, the researchers used temporal-interference stimulation on the spinal cords of rats during opioid overdoses to control their diaphragms and induce breathing. Emitting frequencies of 5,000 and 5,001 hertz through electrodes placed on rats’ necks, the team instantly caused the rodents to breathe at a rate of once per second. The technique also worked when the rats had spinal-cord injuries — which can paralyze the diaphragm and halt breathing — if the electrodes were surgically implanted.
The researchers also used computational models to demonstrate that the point of intersection between the waves can be “steered” left or right without moving the electrodes by varying their relative currents. The steering technique is “something unique to temporal-interference stimulation,” said Sunshine, who is now a postdoctoral researcher in the department of physical therapy at the University of Florida.
“In animals that are no longer breathing following opioid overdose, we showed that using what we call minimally invasive electrodes — electrodes I've just placed on the neck musculature — we could deliver these electric fields to the spinal cord to then restore ventilation, without having to do a surgical approach,” Sunshine said.
The researchers said their application of temporal-interference stimulation could have advantages over naloxone and other first-response treatments for opioid overdoses. The experimental treatment would work for overdoses caused by a cocktail of drugs or non-opioid substances, unlike naloxone, and would avoid the rapid-withdrawal side effects such as seizures and heart-rate irregularities that the medication can cause, the study says.
The electrodes would also be easily and quickly applied, and the method’s ability to induce breathing immediately could be used as a backup option or to make time to prepare other treatments, the authors said.
“As a discovery science project, this opened up a whole new avenue for exploration where we think it could yield some improvements on the current tech,” Fuller said.
The treatment of opioid overdoses is early in its development and has not yet been tested in humans, with no plans currently in the works, Fuller said. But he thinks it would be easier to apply to humans because their central nervous systems are much larger than those of rats and could be targeted more precisely without accidentally activating other motor neurons.
Sunshine said he is collaborating with other researchers to develop other applications for temporal interference, and Fuller wants to try similar tests to see whether the technique still works with the first commercially available stimulation device, which is produced by a company founded by the MIT-based inventors of temporal-interference stimulation.
The professor also said his lab is researching the bodily mechanisms behind the experimental treatment by studying how the rats’ neurons and muscle fibers behave during the wave-interference signals.
“I think both Michael and I feel like there's a little more work to be done in the animals first,” Fuller said, “but that is certainly a goal, to see if that actually can translate and be used to activate human respiratory muscles.”
The article "Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation" was published Jan. 25 in Communications Biology. The authors of the study were Michael Sunshine, Thomas Mareci, Kevin Otto and David Fuller, University of Florida; Antonino Cassarà and Esra Neufeld, Foundation for Research on Information Technologies in Society; Nir Grossman, Imperial College London; and Edward Boyden, Massachusetts Institute of Technology. The lead author was Michael Sunshine.