Ultrasound neurotechnologies are moving quickly into clinical trials in a wide variety of applications, and initiatives to open-source their manufacture will make them more accessible.
The medical community rarely considers prescribing sounds as healing agents. Yet the technology and its potential to treat certain conditions have been known for decades. The therapeutic benefits of high-intensity focused ultrasound (FUS), for instance, were explored in trials in the 1950s1,2. Physicians used it as a non-surgical means to destroy specific areas of the brain to treat movement disorders, psychiatric disorders and brain tumors. In FUS, multiple high-frequency sound waves are made to converge on a specific target within the body, causing tissue modification or destruction. Because it is non-invasive, this technology has the potential to treat a wide variety of conditions and lesions, even those deep inside the brain, without the need for incisions. In clinical practice, FUS has been used to destroy kidney stones, cataracts and tumors, but a new wave of ultrasound-based technologies promises to widen its remit, particularly in the brain.
The US Food and Drug Administration (FDA) has already approved high-intensity focused ultrasound to treat essential tremor and tremor-dominant Parkinson’s disease and to thermally ablate certain tumors. However, low-intensity focused ultrasound (LIFU) is proving to have a broader clinical appeal. LIFU can modulate neuronal activity, inhibiting neurons in brain regions that drive psychiatric illness or chronic pain without causing cell death or damage. A number of clinical trials are testing whether LIFU can inhibit brain areas known to be involved in post-traumatic stress disorder, anxiety and depression3.
Another advantage over high-intensity sounds waves is that LIFU can safely — and temporarily — open the blood–brain barrier (BBB) through mechanical stimulation, providing a means for delivery of gene therapies, drugs or chemotherapies that are too big and cumbersome to penetrate the BBB into the brain. How to deliver agents — gene therapies, small molecules, peptides, antibodies or RNA — past the BBB has long stumped drug makers. Some solutions may harness physical mechanisms rather than chemical reactions. Microbubbles injected into the bloodstream are activated by LIFU as they flow through the brain, temporarily loosening the barrier and allowing gene therapy vectors to pass4. Opening the BBB with ultrasound can also activate microglia, which respond by clearing debris in the brain5.
Ultrasound devices to open the BBB can enhance agents’ delivery into the brain, and several have entered clinical trials. The NaviFUS6 device from NaviFUS received an investigational device exemption from the FDA last year to open the BBB in the treatment of recurrent glioblastoma. The device is also in clinical trials in Taiwan for both glioblastoma and drug-resistant epilepsy, with more trials to launch soon in the United States, Taiwan and Australia. The SonoCloud-9 device from Carthera completed an international phase 1/2 clinical trial in patients with recurrent glioblastoma7 and has moved into phase 3, which will compare the device combined with chemotherapy to standard of care. Moving beyond glioblastoma, a recent study showed that repeated, short-interval treatments to open the BBB without additional administration of medication in Alzheimer’s disease resulted in global amyloid decrease in a small number of people8. Similar systems from InSightec and Columbia University are being tested to open the BBB for monoclonal antibody delivery in patients with Alzheimer’s disease9,10.
Other physical technologies are moving into the neurotech space. Non-invasive neurostimulation techniques could be particularly well suited to targeting rhythmic neural circuits involved in sensory processing, attention and memory. In treatment-resistant epilepsy11, audio-visual or multi-sensory stimuli that regularly flicker on and off can modulate these brain rhythms. Flickering lights were shown to have beneficial effects on mice with Alzheimer’s-like conditions in 2016 (ref. 12), and the same pathways can be activated by flickers in humans13. Individuals with Alzheimer’s disease have weaker gamma-frequency brain waves, crucial for forming memories. Rhythmic stimulation modifies neuronal firing patterns, leading to molecular debris clearance in the brain. Cognito Therapeutics is trialing the technology in the clinic, recently posting strong safety profiles and improved patient cognitive function in a phase 2 clinical trial, and hoping to move to clinical trials with Parkinson’s disease and multiple sclerosis.
It is not clear exactly how all these therapies work. Some hypothesize that mechanical forces disrupt the cellular membrane conformation, leading to polarization and activating channels or proteins embedded within; others point at evidence suggesting that the ultrasound could directly cause membrane channels to activate. The reality is likely to be combinations of these mechanisms in different tissues14. Since many core neural networks involved in neurological disease progression are still unclear, a highly precise ultrasound therapy will be difficult to use effectively. Multisensory flickers are most effective in the brain’s primary sensory regions, and the effects are currently modest: longer or repeated exposures may be necessary to enhance clinical outcomes for harder-to-reach brain areas. Opening the BBB promises to make drug delivery more efficient, but it is not clear how much drug is clearing the barrier, nor how dosing should be performed.
Even as clinical trials produce promising outcomes, it is unclear how many of these therapies will be able to move into standard of care. Non-invasive ultrasound technology has been around for decades, but only two applications have been approved by the FDA. A complex medical device costs hundreds of millions of dollars to manufacture. Transitioning a neurodevice from a research lab setting through the multiple stages of human clinical trials involves substantial scaling up of production. Most labs do not have enough funding, so in-house devices rarely make it to the FDA.
This bottleneck is now being addressed directly. Openwater is a medical technology startup that is focused on manufacturing neurotech devices that scale quickly and inexpensively. Instead of focusing on a specific disease indication, they develop modular LIFU devices that can be used on any part of the body with slight modifications. Their platform combines high-resolution infrared imaging, ultrasound and targeted electromagnetic fields with visualization and monitoring. Studies in mice showed promising results, shrinking glioblastoma and treating depression15 and stroke16 in humans, with more clinical results pending.
For an even larger impact, Openwater declared in January 2024 that the technology would be open source: the hardware blueprints, source code, patents, and clinical and safety data are all available to anyone who wants to use them. The company makes money selling their hardware and services directly to those who do not wish to make their own devices; Openwater’s manufacturing through already established supply chains relieves researchers of expensive product development costs. When the safety data are shared across trials, trial costs are also reduced for the researchers. (Openwater does not fund the trials or take ownership of regulatory approvals.) With this strategy, instead of the eye-watering $658 million investment over 13 years for any new medical device to reach the market, precision electronics and resonance-based therapies would need $10 million over 3 years to reach commercialization. Coupled with the open source model, these medical technologies could make healthcare solutions affordable in record time.
