The mantra a generation ago is that bigger was better. And it holds for things that make life easy, like free meals and your bank balance. But a new cohort of research engineers is realising that to solve some of the biggest biological problems, like treating depression, the opposite is true: smaller could be the winner.
So realised Tiago Costa, a microelectronics researcher based at Delft University of Technology (TU Delft) in the Netherlands. His interest in depression research arose from the practical realisation that ultrasound technology could be miniaturised and tuned to modulate neurons deep in the brain. “Normally you see ultrasound as a bulky cart in a hospital,” he explains, “but we can now shrink that into a chip the size of a fingernail.”
Tiago was wondering what the best application for tiny ultrasound would be when he got talking to a neurosurgeon who laid it out straight, telling him that in the neurotech space, doctors do not have a good solution for two conditions – chronic pain and depression. “When I later talked to expert depression researchers at the University of Freiburg, they said, ‘This is perfect’. These key moments told me this is the way to go.”
Tiago then got the European Innovation Community Pathfinder funding to create Project UPSIDE, a collaborative initiative to develop and harness miniature ultrasound chips to act like tiny, phased arrays: focusing pressure waves inside the mind like a spotlight shining on specific areas of grey matter, without having to drive invasive electrodes deep into neural tissue.
A lifeline to transform treatment
Depression remains one of the most pervasive global health problems. Depressive disorders are set to become the world’s leading cause of disability by 2030. In Europe, around 10% of women over 45 suffer from chronic depression, and an estimated 120,000 people take their own lives in the WHO European Region, equivalent to 1.3% of all deaths. Almost one-third of patients who do not respond to two or more antidepressant regimens will attempt suicide. This is all despite antidepressant consumption nearly doubling between 2000 and 2017 in OECD countries: for at least half of depression sufferers, the drugs don’t work.
For people who do not respond to exercise, talking therapies, or antidepressant drugs – at least one third of patients – the options are limited. Deep brain stimulation (DBS) involves electrodes implanted directly into the brain and has shown promise in treatments for Parkinson’s, but it is invasive, costly, and, because it involves major surgery, is not without risks. For depression, DBS success rates vary highly from person to person, or do not work at all.
Transcranial approaches, in contrast, are less intrusive but cumbersome, often involving bulky helmets and hospital visits. Tiago points to clinical trials showing that if patients go there once a week or follow a specific protocol, they can get better. But there’s also evidence that if patients stop going to the hospital after a while, the symptoms come back.
That’s why Tiago and his team favour the middle road – a minimally invasive implant placed under the skull but without penetrating the brain that does not carry the risks of major DBS surgery. “The patients can go about their daily life, attend many fewer hospital visits, and the machine is working for them all the time, and they are unaware of it,” he says.
Making this a reality requires four carefully crafted steps. The first two are complete: creating a miniaturised ultrasound chip at TU Delft, and developing a recording chip using ultra-precise microelectrodes engineered by the project’s partners at Ghent University to measure ultrasound feedback from inside the brain. This is needed to decode the data from the brain and try to identify biomarkers of depression, the ultimate aim being to then use the data and biomarkers to better direct the pressure waves within the brain to the areas where the best clinical effect is predicted.
Phase three is underway to evaluate both chips in animal models. This is led by Project UPSIDE partners at the University of Freiburg, who are experts in clinical trials in humans, and pre-clinical research in rats and depression, utilising rodent phenotypes that show symptoms and physical markers of depression, and most importantly, when a treatment is working as expected. After that, a larger animal model will be required. “The leap from rats to humans is too great,” says Tiago. “We need an intermediate step like sheep where the brain is closer in size and complexity.” At the same time, every material and component is being scrutinised for human biocompatibility to comply with European Medical Agency requirements, in the hope of eventually gaining approval for human clinical trials.
Tiago says the project has opened his mind to new perspectives, particularly in the way sufferers live with depression. He says:
“After some press releases, I started to get emails from depression patients. I had no idea it was so many people. Now I see the severity, I’m even more driven after these three years that we have been working on it.”
Perfect partners for progress
Tiago credits the progress made so far with the right consortia partners and the right funding mechanism. Just three universities sharing the grant means less coordination, less admin, more experimental work. He says the Pathfinder funding is a “perfect match” for the project’s aims, taking readiness level (TRL) from 2-3 up to four and beyond. “It’s not common to have such substantial funding for a small team to do something that has this kind of impact,” says Tiago.
“It confirmed that the ideas had value, not just in my head but in the eyes of colleagues and reviewers.”
For all the progress, the project has had many challenges from Covid-19 hiring issues to bespoke items in the supply chain with long manufacturing times being in short supply: when the project started, the two completed chips simply did not exist. Now Tiago is looking for an EIC Transition grant to take the TRL up to five, gearing up to present production partnerships with researchers in Italy (Newronika) and suppliers in Portugal (SiliconGate). A US-based non-profit, the Focus Ultrasound Foundation, lends additional global perspective, supporting the present community and advocating for a future where tens, hundreds of thousands of people or more could be wearing such implants.
Public perception often lurches toward science fiction, like fears of brain-hacking or mind-reading. But Tiago is quick to temper such concerns. The chips, he points out, have extremely limited processing power. “It’s good to question, but many fears are overblown,” he says.
Photo by Pawel Czerwinski on Unsplash
