Ultrasound-activated nanoparticles provide targeted control of brain activity

10 Dec 2018 James Bezer
Drug uncaging
Nanoparticle-mediated ultrasonic drug uncaging can noninvasively modulate brain activity. (Courtesy: Raag Airan et al)
Drug uncaging

Researchers at Stanford University have developed a technique to non-invasively control activity in specific regions of the brain, using drug-loaded nanoparticles activated by a focused beam of ultrasound (Neuron 10.1016/j.neuron.2018.10.042).

Precise control of activity in specific regions of the brain is a major goal in the treatment of many neurological and psychiatric disorders, as well as in neuroscientific research. Currently, localized control of brain function either requires electrodes to be implanted directly into the brain, which is extremely invasive, or use of trans-cranial magnetic or acoustic stimulation of neurones. Such stimulation is imprecise, has a limited range of effects and has an unclear mechanism of action.

The Stanford researchers have demonstrated a new non-invasive approach for targeted control of brain activity. They embedded the anaesthetic propofol inside polymer nanoparticles, which are about 400 nm in diameter and can be injected intravenously in solution. When in the blood, the drug usually remains encased inside the nanoparticles. However, when exposed to ultrasound, the nanoparticles break up, releasing the drug, which can then diffuse into the surrounding tissues.

The ultrasound pulse can be focused onto a specific target area, meaning that, unlike with conventional anaesthesia, the drug’s effects are localized only to precise regions of the brain.

The team tested the technique on rats, by focusing ultrasound onto the animal’s visual cortex. The brain’s response to visual stimuli was recorded using electrodes, and the visual cortex showed significantly reduced activity after treatment. Activity in the motor cortex was unaffected, however, demonstrating that the response to the procedure was localized.

The researchers also performed PET scans to identify which regions of the brain were taking up most glucose and therefore had more activity. They saw that other, distant regions of the brain associated with those deactivated areas had their activity affected too. The authors suggest that the technique could therefore be used as a way of mapping interactions between different parts of the brain.

Unlike more common techniques to control brain activity, this approach is non-invasive, has a clear mechanism, and could in future be used with different drugs to generate a wide range of effects.

To check the safety of the process, the authors also looked for any adverse effects due to the ultrasound or nanoparticles, such as haemorrhaging or disruption of the blood-brain barrier. Raag Airan, whose group conducted the research, comments: “We have now completed ultrasonic drug uncaging in over 100 rats without evidence of significant toxicity or parenchymal [tissue] damage. It seems we have a wide window of safe ultrasound parameters that we can use with these nanoparticles.”

Ultrasound has been widely used in medical imaging for decades, but its applications in drug delivery have only recently been realized. While this is the first study to use the technique to control brain activity, ultrasound-triggered drug release has previously been used to improve the effectiveness and safety of chemotherapy drugs, and clinical trials in humans are currently ongoing.

There are still some regulatory hurdles to overcome before this particular technique can be safely tested on humans, but Airan is optimistic about its clinical potential.

“The first trial we’re looking to do is to localize epileptogenic regions in the brain of patients with treatment resistant epilepsy who are slated for neurosurgery, to validate that the intended surgical volume is indeed the generator of abnormal brain activity – and to ensure that removing it wouldn’t induce an unexpected functional deficit like aphasia or amnesia,” Airan says. “While it is speculative to say when this might come together, I think it is reasonable for us to expect this trial to start within about three years”