Ultrasound is most familiar to us as a non-invasive imaging technology used during pregnancy – now it is in clinical trials as a powerful new tool for treating all sorts of medical conditions.
IMAGINE a medical device that could treat an enormous range of our ills, both big and small. A gadget that showed promise for destroying cancerous tumours or obliterating the body fat associated with obesity. Or that was potentially effective against the likes of back pain and glaucoma – and that was even versatile enough to be considered as a tool for tackling depression or anxiety. Surprisingly, such technology exists. Even more surprisingly, it works simply by generating sound waves.
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| Ryan Wills |
While perhaps most familiar to us for its use in medical imaging, ultrasound has emerged in recent decades as an extraordinarily flexible medical tool. Using the heat that intense ultrasound waves generate, we can destroy tumours or other problematic tissue deep within the body without making any incisions. Dial down the intensity, meanwhile, and we can gain unprecedented access to the brain, shaking cells to change their behaviour in ways that seem to improve mental health. For good measure, ultrasound may even reverse signs of physical ageing and reduce the learning and memory problems associated with older age.
“Ultrasound is already a ubiquitous tool in medicine,” says Nir Lipsman at Sunnybrook Research Institute in Toronto, Canada. “But there’s tremendous focus on it right now because of the different ways we could use it to treat different medical problems.”
The potential applications are coming so thick and fast that they are outpacing our ability to understand why it is so effective. The question now is: can we figure out how ultrasound affects our cells, so the technology can reach its full potential?
Medical imaging
Ultrasound – high-frequency sound above 20 kilohertz – is widely used for medical imaging. But we have known for decades that it can do much more. Back in the 1940s and 50s, William and Francis Fry at the University of Illinois discovered that ultrasound could also function as a surgical tool. The brothers developed a device that focused ultrasound from several directions onto a single spot within tissue. The localised heat this generated destroyed cells at the target site while leaving surrounding tissue unharmed.
By the early 1960s, the Fry brothers and their colleagues were using high-intensity focused ultrasound (HIFU) to target and destroy unhealthy tissue in human brains to treat symptoms associated with Parkinson’s disease with some success.
“You can focus ultrasound to different lengths and, in doing so, you can target deeper brain regions in ways you can’t with other technologies,” says Wynn Legon at Virginia Tech.
More applications followed later in the 20th century. Some researchers began exploring whether HIFU could destroy cancerous tumours, both in animals and in people. Others began using it in eye surgery.
It was the tip of the iceberg. Today, the range of potential applications is truly extraordinary. Alongside its use for treating various cancers, including prostate cancer, there is evidence that HIFU can be used to treat back pain. Preclinical trials, meanwhile, show that the technology can destroy body fat below the skin, suggesting a possible use in treating obesity. And for a few hundred pounds, anyone can buy a personal HIFU system designed to treat wrinkles.
The fact that HIFU is non-invasive and can precisely hit a target helps explain why it is so useful, says Legon. “It means it can be used for a wide variety of different purposes.”
Its precision makes it particularly handy in the brain. When the Fry brothers and their colleagues first began using the technology to treat Parkinson’s, it was necessary to remove a small piece of the skull because bone interferes with the ability to focus ultrasound waves. But about 30 years ago, researchers overcame this obstacle. They developed more advanced devices that can manipulate the ultrasound waves to adjust for the thickness of an individual’s skull, meaning it was no longer necessary to remove any bone. The development allowed researchers to experiment with HIFU as a therapy for a broader range of conditions. For instance, used to target small areas of the limbic system – which plays a role in processing emotions – HIFU can help treat obsessive-compulsive disorder.
Lipsman says that the list of HIFU applications may grow even longer, “provided you know where to target the ultrasound to get the effects you need”.
But there is another side to ultrasound. Back in the late 1950s, when the Fry brothers were developing their technology, they made another discovery. When they dialled down the intensity of the ultrasound, they could change the way cells behave without destroying them. For instance, tests in cats showed that applying what became known as low-intensity focused ultrasound (LIFU) to a region of the brain involved in vision – the lateral geniculate nucleus – temporarily reduced the animals’ ability to respond to light.
Therapy for depression
“That was groundbreaking research,” says Legon. But, he says, for some reason, the idea of manipulating cells with LIFU “never really took off”. Not until 2010, however, when William Tyler at Arizona State University and his colleagues showed that LIFU delivered to the motor cortex of mice made their paws or tails twitch. The work indicated that this type of ultrasound could stimulate neurons in a precise brain region without requiring surgically implanted electrodes. “People started to get excited about it again,” says Legon.
Within a few years, Tyler, Legon and their colleagues were exploring the effects of LIFU on humans. Applied to the somatosensory cortex, an area of the brain that receives signals from the skin, LIFU improved volunteers’ skin sensitivity. Focused instead on the primary motor cortex, it boosted reaction times by a few milliseconds. Buoyed by such discoveries, researchers are now exploring whether LIFU can tweak the behaviour of brain cells to treat a range of conditions. Several clinical trials are under way to explore whether it is an effective therapy for depression, anxiety, epilepsy or post-traumatic stress disorder. Legon, meanwhile, began a clinical trial last year to understand how LIFU may help people manage pain. He says the early results are encouraging, although there is more to do before it becomes a viable therapy.
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| Ultrasound is used in a trial to treat symptoms of Parkinson’s disease Kevin Van Paassen/Sunnybrook Health Sciences Centre |
But it is another application of LIFU that is arguably generating the greatest buzz. Ultrasound waves aren’t just useful for manipulating cells, they can also be used to open the blood-brain barrier. This semipermeable membrane surrounds the specialised system of blood vessels in the brain, where it prevents pathogens and other substances in the blood from crossing into neural tissue. The problem is that the blood-brain barrier also keeps about 98 per cent of drugs out of the brain, which has long been an obstacle to the treatment of conditions in this part of the body, including cancer and Alzheimer’s disease.
Over the past 20 years, researchers have begun to exploit the fact that LIFU shakes anything under its focus. They now inject 0.5 to 1-micrometre-wide bubbles filled with air or another gas into the bloodstream and then use LIFU to agitate them as they pass through blood vessels in the brain. Doing so bursts the bubbles, and the resulting shock wave temporarily disrupts the blood-brain barrier, allowing drugs or other molecules to enter brain tissue.
Lipsman was part of a team that first used the technique to open the human blood-brain barrier in 2015. Since then, the technology has been used in clinical trials to treat brain tumours. Jeffrey Kordower at Arizona State University is working to use LIFU and microbubbles to bring gene therapies into the brain to treat Parkinson’s disease. His team isn’t there yet, but Kordower says the approach shows great promise.
“Once we get to the point where we can get specific gene therapies across the blood-brain barrier, it could be a one-and-done treatment for many neurodegenerative diseases,” he says.
Because this barrier is two-way, opening it also offers an opportunity to flush out problematic proteins and other products that accumulate in the brain. Jürgen Götz at the University of Queensland, Australia, and his colleagues used a form of LIFU with microbubbles to clear the amyloid deposits associated with Alzheimer’s from mice altered to have a version of this disease.
Lipsman, meanwhile, is currently using the LIFU-microbubble combination to “actively pump” DNA markers from glioblastoma tumours through the blood-brain barrier and into the general bloodstream. From there, it is easier for clinicians to sample them to monitor an individual’s response to cancer treatment.
“We’re currently doing an initial trial in humans and, if successful, it may open up a new way for us to monitor disease progression in the brain,” says Lipsman.
However, the most recent developments with LIFU are perhaps the most surprising. They suggest that it can rejuvenate brain cells and potentially reverse signs of ageing elsewhere in the body.
As mammals age, their brains lose the ability to process new information, creating problems with learning and memory. Götz and his team wondered whether LIFU could help reverse this decline. Their idea was to use it, alongside microbubbles, to open the blood-brain barrier and allow a range of yet-to-be-identified blood-borne products into the brain. These products appear to help improve the performance of cells by, among other things, clearing protein aggregates from the brain.
Reversing ageing
Studies in mice confirmed their idea – up to a point. The mice that had their blood-brain barrier opened using this technique did indeed experience the predicted benefits in brain cell performance. But Götz and his colleagues were surprised to find that a group of mice given LIFU alone (whose blood-brain barrier remained closed) actually fared even better: not only was long-term potentiation restored in these mice, their ability to learn new information about their environment also improved. That learning boost wasn’t seen in the mice whose blood-brain barrier was opened – and it isn’t clear why.
“It was absolutely fascinating,” says Götz. The research has prompted him and his colleagues to consider trialling the technology in older people to see whether it has similar effects on learning.
Michael Sheetz at the University of Texas Medical Branch and his colleagues have made similarly intriguing discoveries. In a study put online late last year ahead of formal peer review, they found that exposing aged – or “senescent” – animal cells in a dish to low-frequency ultrasound rejuvenates them, encouraging them to grow and divide in a similar way to young cells. Remarkably, the effects even seemed to translate to whole animals: ageing mice placed in a bath of warm water and exposed to low-frequency ultrasound began to behave more like young mice. In one case, a mouse with a hunched back and mobility problems began to move normally again after treatment.
“I’ll admit to asking myself whether the results were too good to be true, but they speak for themselves,” says Sheetz. “The ultrasound appears to be reversing senescence in these animals. What remains to be seen is whether it can do the same in humans.”
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| Ultrasound imaging can help identify a prostate tumour (pink) ZEPHYR/SCIENCE PHOTO LIBRARY |
He is now planning a trial involving people with osteoarthritis or diabetes, both of which can be associated with aged cells. But even as researchers begin to dream about clinical applications, they continue to be puzzled about exactly how LIFU – and low-frequency ultrasound more generally – produces such remarkable results.
“Is it a mechanical mechanism? A physical one? Thermal? What is it doing, exactly? That’s still being investigated,” says Legon.
He suspects mechanical forces are important. As low-intensity ultrasound waves wash over cells, they induce small pressure changes within the tissue. Research suggests this can influence some of the receptor channels on brain cells, changing how the cells behave and communicate with one another.
Sheetz believes the mode of action in his ageing mice is different. He thinks pressure changes from ultrasound waves can push and pull senescent cells, giving them a sort of physical workout. This activates a dormant process called autophagy that allows the cells to dispose of poorly functioning components and return to good working order.
“A major factor in senescence is that autophagy is blocked,” he says. “It appears that ultrasound is somehow activating the autophagy pathway in senescent cells, allowing the cells to clean out the debris and go back to more normal behaviour.”
There are other proposed mechanisms. A 2019 study suggested that LIFU influences brain tissue via star-shaped brain cells called astrocytes that, among other things, provide support for neurons.
In a review published earlier this year, Götz and his colleagues suggest that one, several or even all of these hypotheses could be correct. “Depending on what kind of ultrasound you are using, what part of the brain you are targeting and what pathology is there, you may see different effects,” he says.
Even once we understand how low-frequency ultrasound works, there are other problems to overcome before the technology will be on offer at your local hospital, says Legon. In particular, there is the matter of addressing how long the effects of the treatments last.
“A lot of the current research shows that the effects last an hour, maybe two, depending on how long you deliver the ultrasound,” he says. “For clinical translation, we’d need to see a longer-lasting effect.”
Even Sheetz’s rejuvenated mice quickly revert to their feebler states once they stop receiving ultrasound. “This is not something where we can give one treatment and it solves the problem,” he says.
But Legon remains optimistic. He says that when you look at other methods of influencing cell behaviour, like transcranial magnetic stimulation, it took decades to tweak the technology and help it reach its full potential.
Optimising takes so long partly because there are so many variables at play, says Lipsman – not least varying the strength and duration of treatment. “The versatility of this technology is a double-edged sword,” he says. But he thinks the ultimate payoff will be worth the effort. “This is a technology where we could press many levers to solve different problems. Ultrasound holds tremendous promise.”