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Shonagh Rae
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Inflammation: It’s the body’s natural response to injury and infection, but medical science now recognizes it as a double-edged sword. When inflammation becomes chronic, it can contribute to a host of serious health problems, including arthritis, heart disease, and certain cancers. As this understanding has grown, so too has the search for effective ways to manage harmful inflammation.
Doctors and researchers are exploring various approaches to tackle this pervasive health issue, from new medications to dietary interventions. But what if one of the most promising treatments relies on a familiar technology that’s been in hospitals for decades?
Enter focused ultrasound stimulation (FUS), a technique that uses sound waves to reduce inflammation in targeted areas of the body. It’s a surprising new application for ultrasound technology, which most people associate with prenatal checkups or diagnostic imaging. And FUS may help with many other disorders too, including diabetes and obesity. By modifying existing ultrasound technology, we might be able to offer a novel approach to some of today’s most pressing health challenges.
Our team of biomedical researchers at the Institute of Bioelectronic Medicine (part of the Feinstein Institutes for Medical Research), in Manhasset, N.Y., has made great strides in learning the electric language of the nervous system. Rather than treating disease with drugs that can have broad side effects throughout the body, we’re learning how to stimulate nerve cells, called neurons, to intervene in a more targeted way. Our goal is to activate or inhibit specific functions within organs.
The relatively new application of FUS for neuromodulation, in which we hypothesize that sound waves activate neurons, may offer a precise and safe way to provide healing treatments for a wide range of both acute and chronic maladies. The treatment doesn’t require surgery and potentially could be used at home with a wearable device. People are accustomed to being prescribing pills for these ailments, but we imagine that one day, the prescriptions could be more like this: “Strap on your ultrasound belt once per day to receive your dose of stimulation.”
How Ultrasound Stimulation Works
Ultrasound is a time-honored medical technology. Researchers began experimenting with ultrasound imaging in the 1940s, bouncing low-energy ultrasonic waves off internal organs to construct medical images, typically using intensities of a few hundred milliwatts per square centimeter of tissue. By the late 1950s, some doctors were using the technique to show expectant parents the developing fetus inside the mother’s uterus. And high-intensity ultrasound waves, which can be millions of milliwatts per square centimeter, have a variety of therapeutic uses, including destroying tumors.
The use of low-intensity ultrasound (with intensities similar to that of imaging applications) to alter the activity of the nervous system, however, is relatively unexplored territory. To understand how it works, it’s helpful to compare FUS to the most common form of neuromodulation today, which uses electric current to alter the activity of neurons to treat conditions like Parkinson’s disease. In that technique, electric current increases the voltage inside a neuron, causing it to “fire” and release a neurotransmitter that’s received by connected neurons, which triggers those neurons to fire in turn. For example, the deep brain stimulation used to treat Parkinson’s activates certain neurons to restore healthy patterns of brain activity.
How It Works
In focused ultrasound stimulation, we theorize that sound waves’ vibrations (1) cause channels (2) on the neuron’s cell membrane to open. Positive ions flow in, causing a voltage change within the neuron that triggers it to fire with an action potential (3) that travels down the axon. The axon’s tips (4) release neurotransmitters that cause connected neurons to fire in turn.
Chris Philpot
In FUS, by contrast, the sound waves’ vibrations interact with the membrane of the neuron, opening channels that allow ions to flow into the cell, thus indirectly changing the cell’s voltage and causing it to fire. One promising use is transcranial ultrasound stimulation, which is being tested extensively as a noninvasive way to stimulate the brain and treat neurological and psychiatric diseases.
We’re interested in FUS’s effect on the peripheral nerves—that is, the nerves outside the brain and spinal cord. We think that activating specific nerves in the abdomen that regulate inflammation or metabolism may help address the root causes of related diseases, rather than just treating the symptoms.
FUS for Inflammation
Inflammation is something that we know a lot about. Back in 2002, Kevin Tracey, currently the president and CEO of the Feinstein Institutes, upset the conventional wisdom that the nervous system and the immune system operate independently and serve distinct roles. He discovered the body’s inflammatory reflex: a two-way neural circuit that sends signals between the brain and body via the vagus nerve and the nerves of the spleen. These nerves control the release of cytokines, which are proteins released by immune cells to trigger inflammation. Tracey and colleagues found that stimulating nerves in this neural circuit suppressed the inflammatory response. The discoveries led to the first clinical trials of electrical neuromodulation devices to treat chronic inflammation and launched the field of bioelectronic medicine.
Hacking the Immune System
When focused ultrasound (1) is applied to the spleen (2), it activates neurons (3), causing them to release certain neurotransmitters that interact with immune cells called T-cells (4) and macrophages (5). Those interactions release another neurotransmitter that binds to receptors on the macrophages, inhibiting them from producing and releasing cytokines, thus putting the brakes on the inflammatory response.
Chris Philpot
Tracey has been a pioneer in treating inflammation with vagus nerve stimulation (VNS), in which electrical stimulation of the vagus nerve activates neurons in the spleen. In animals and humans, VNS has been shown to reduce harmful inflammation in both chronic diseases such as arthritis and acute conditions such as sepsis. But direct VNS requires surgery to place an implant in the body, which makes it risky for the patient and expensive. That’s why we’ve pursued noninvasive ultrasound stimulation of the spleen.
Working with Tracey, collaborators at GE Research, and others, we first experimented with rodents to show that ultrasound stimulation of the spleen affects an anti-inflammatory pathway, just as VNS does, and reduces cytokine production as much as a VNS implant does. We then conducted the first-in-human trial of FUS for controlling inflammation.
We initially enrolled 60 healthy people, none of whom had signs of chronic inflammation. To test the effect of a 3-minute ultrasound treatment, we were measuring the amount of a molecule called tumor necrosis factor (TNF), which is a biomarker of inflammation that’s released when white blood cells go into action against a perceived pathogen. At the beginning of the study, 40 people received focused ultrasound stimulation, while 20 others, serving as the control group, simply had their spleens imaged by ultrasound. Yet, when we looked at the early data, everyone had lower levels of TNF, even the control group. It seemed that even imaging with ultrasound for a few minutes had a moderate anti-inflammatory effect! To get a proper control group, we had to recruit 10 more people for the study and devise a different sham experiment, this time unplugging the ultrasound machine.
Shonagh Rae
After the subjects received either the real or sham stimulation, we took blood samples from all of them. We next simulated an infection by adding a bacterial toxin to the blood in the test tubes, then measured the amount of TNF released by the white blood cells to fight the toxin. The results, which we published in the journal Brain Stimulation in 2023, showed that people who had received FUS treatments had lower levels of TNF than the true control group. We saw no problematic side effects of the ultrasound: The treatment didn’t adversely affect heart rate, blood pressure, or the many other biomarkers that we checked.
The results also showed that when we repeated the blood draw and experiment 24 hours later, the treatment groups’ TNF levels had returned to baseline. This finding suggests that if FUS becomes a treatment option for inflammatory diseases, people might require regular, perhaps even daily, treatments.
One surprising result was that it didn’t seem to matter which location within the spleen we targeted—all the locations we tried produced similar results. Our hypothesis is that hitting any target within the spleen activates enough nerves to produce the beneficial effect. What’s more, it didn’t matter which energy intensity we used. We tried intensities ranging from about 10 to 200 mW per cm2, well within the range of intensities used in ultrasound imaging; remarkably, even the lowest intensity level caused subjects’ TNF levels to drop.
Our big takeaway from that first-in-human study was that targeting the spleen with FUS is not just a feasible treatment but could be a gamechanger for inflammatory diseases. Our next steps are to investigate the mechanisms by which FUS affects the inflammatory response, and to conduct more animal and human studies to see whether prolonged administration of FUS to the spleen can treat chronic inflammatory diseases.
FUS for Obesity and Diabetes
For much of our research on FUS, we’ve partnered with GE Research, whose parent company is one of the world’s leading makers of ultrasound equipment. One of our first projects together explored the potential of FUS as a treatment for the widespread inflammation that often accompanies obesity, a condition that now affects about 890 million people around the world. In this study, we fed lab mice a high-calorie and high-fat “Western diet” for eight weeks. During the following eight weeks, half of them received ultrasound stimulation while the other half received daily sham stimulation. We found that the mice that received FUS had lower levels of cytokines—and to our surprise, those mice also ate less and lost weight.
In related work with our GE colleagues, we examined the potential of FUS as a treatment for diabetes, which now affects 830 million people around the world. In a healthy human body, the liver stores glucose as a reserve and releases it only when it registers that glucose levels in the bloodstream have dropped. But in people with diabetes, this sensing system is dysfunctional, and the liver releases glucose even when blood levels are already high, causing a host of health problems.
Hacking the Metabolic System
When focused ultrasound (1) is applied to an area in the liver (2) called the porta hepatis, it activates glucose-sensing neurons. Those neurons send signals up the vagus nerve (3) to the brain, where a region called the hypothalamus (4) commands the body to reduce glucose production and increase glucose uptake.
Chris Philpot
For diabetes, our ultrasound target was the network of nerves that transmit signals between the liver and the brain: specifically, glucose-sensing neurons in the porta hepatis, which is essentially the gateway to the liver. We gave diabetic rats 3-minute daily ultrasound stimulation over a period of 40 days. Within just a few days, the treatment brought down the rats’ glucose levels from dangerously high to normal range. We got similar results in mice and pigs, and published these exciting results in 2022 in Nature Biomedical Engineering.
Those diabetes experiments shed some light on why ultrasound had this effect. We decided to zero in on a brain region called the hypothalamus, which controls many crucial automatic body functions, including metabolism, circadian rhythms, and body temperature. Our colleagues at GE Research started investigating by blocking the nerve signals that travel from the liver to the hypothalamus in two different ways—both cutting the nerves physically and using a local anesthetic. When we then applied FUS, we didn’t see the beneficial decrease in glucose levels. This result suggests that the ultrasound treatment works by changing glucose-sensing signals that travel from the liver to the brain—which in turn changes the commands the hypothalamus issues to the metabolic systems of the body, essentially telling them to lower glucose levels.
The next steps in this research involve both technical development and clinical testing. Currently, administering FUS requires technical expertise, with a sonographer looking at ultrasound images, locating the target, and triggering the stimulation. But if FUS is to become a practical treatment for a chronic disease, we’ll need to make it usable by anyone and available as an at-home system. That could be a wearable device that uses ultrasound imaging to automatically locate the anatomical target and then delivers the FUS dose: All the patient would have to do is put on the device and turn it on. But before we get to that point, FUS treatment will have to be tested clinically in randomized controlled trials for people with obesity and diabetes. GE HealthCare recently partnered with Novo Nordisk to work on the clinical and product development of FUS in these areas.
FUS for Cardiopulmonary Diseases
FUS may also help with chronic cardiovascular diseases, many of which are associated with immune dysfunction and inflammation. We began with a disorder called pulmonary arterial hypertension, a rare but incurable disease in which blood pressure increases in the arteries within the lungs. At the start of our research, it wasn’t clear whether inflammation around the pulmonary arteries was a cause or a by-product of the disease, and whether targeting inflammation was a viable treatment. Our group was the first to try FUS of the spleen in order to reduce the inflammation associated with pulmonary hypertension in rats.
The results, published last year, were very encouraging. We found that 12-minute FUS sessions reduced pulmonary pressure, improved heart function, and reduced lung inflammation in the animals in the experimental group (as compared to animals that received sham stimulation). What’s more, in the animals that received FUS, the progression of the disease slowed significantly even after the experiment ended, suggesting that this treatment could provide a lasting effect.
One day, an AI system might be able to guide at-home users as they place a wearable device on their body and trigger the stimulation.
This study was, to our knowledge, the first to successfully demonstrate an ultrasound-based therapy for any cardiopulmonary disease. And we’re eager to build on it. We’re next interested in studying whether FUS can help with congestive heart failure, a condition in which the heart can’t pump enough blood to meet the body’s needs. In the United States alone, more than 6 million people are living with heart failure, and that number could surpass 8 million by 2030. We know that inflammation plays a significant role in heart failure by damaging the heart’s muscle cells and reducing their elasticity. We plan to test FUS of the spleen in mice with the condition. If those tests are successful, we could move toward clinical testing in humans.
The Future of Ultrasound Stimulation
We have one huge advantage as we think about how to bring these results from the lab to the clinic: The basic hardware for ultrasound already exists, it’s already FDA approved, and it has a stellar safety record through decades of use. Our collaborators at GE have already experimented with modifying the typical ultrasound devices used for imaging so that they can be used for FUS treatments.
Once we get to the point of optimizing FUS for clinical use, we’ll have to determine the best neuromodulation parameters. For instance, what are the right acoustic wavelengths and frequencies? Ultrasound imaging typically uses higher frequencies than FUS does, but human tissue absorbs more acoustic energy at higher frequencies than it does at lower frequencies. So to deliver a good dose of FUS, researchers are exploring a wide range of frequencies. We’ll also have to think about how long to transmit that ultrasound energy to make up a single pulse, what rate of pulses to use, and how long the treatment should be.
In addition, we need to determine how long the beneficial effect of the treatment lasts. For some of the ailments that researchers are exploring, like FUS of the brain to treat chronic pain, a patient might be able to go to the doctor’s office once every three months for a dose. But for diseases associated with inflammation, a regular, several-times-per-week regimen might prove most effective, which would require at-home treatments.
For home use to be possible, the wearable device would have to locate the targets automatically via ultrasound imaging. As vast databases already exist of human ultrasound images from the liver, spleen, and other organs, it seems feasible to train a machine-learning algorithm to detect targets automatically and in real time. One day, an AI system might be able to guide at-home users as they place a wearable device on their body and trigger the stimulation. A few startups are working on building such wearable devices, which could take the form of a belt or a vest. For example, the company SecondWave Systems, which has partnered with the University of Minnesota, in Minneapolis, has already conducted a small pilot study of its wearable device, trying it out on 13 people with rheumatoid arthritis and seeing positive outcomes.
While it will be many years before FUS treatments are approved for clinical use, and likely still more years for wearable devices to be proven safe enough for home use, the path forward looks very promising. We believe that FUS and other forms of bioelectronic medicine offer a new paradigm for human health, one in which we reduce our reliance on pharmaceuticals and begin to speak directly to the body electric.
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