A new study provides the first visual evidence showing that brain circuits in living animals can be activated by ultrasound waves projected into specific patterns (holograms).
Led by scientists at NYU Langone Health and at the University of Zurich and ETH Zurich in Switzerland, the study describes a system that combines sources of ultrasound waves and a fiber scope connected to a camera to visualize in study mice brain targets that are directly activated by the sound. This lays the groundwork, the study authors say, for a new way to treat neurological diseases and mental health disorders from outside of the body.
Already, there are applications approved by the Food and Drug Administration and designed to reduce tremor symptoms seen in Parkinson's disease, using intense sound waves to kill brain cells called neurons within neural pathways linked to tremors. Rather than kill neurons, the lower-intensity ultrasound waves used in the current work can temporarily activate them, the researchers say. The resulting effects can be widespread as neurons relay messages to other neurons within their circuits and between interconnected neuronal circuits.
Directly observing the effects of this technology, called transcranial ultrasound stimulation (TUS), in a living brain is difficult, but studying neurons in a dish in the lab does not accurately reflect the way ultrasound waves travel through the skull or behave in three-dimensional tissue. For TUS therapy to be safe and effective, researchers say, ultrasound waves need to target specific brain areas and must be calibrated so that the signal is strong enough to penetrate the skull, but not so strong as to damage delicate brain tissue.
Published in the journal Nature Biomedical Engineering online July 7, the current study featured experiments performed inside a living brain that accurately replicated how an activated neuron in one part of the brain can have far-reaching effects through connected circuits.
"Our work shows that activating entire sets of neural networks with transcranial ultrasound stimulation in a living mouse brain is possible," said study co-senior author Shy Shoham, PhD. The other co-senior author is Daniel Razansky, PhD, at the University of Zurich and ETH Zurich in Switzerland.
"We also found that, by focusing on circuits of neurons that are distributed across brain regions rather than in any individual region, TUS leverages inter-connections within the circuits to make targeted neurons 10 times more sensitive to ultrasound," said Shoham, who is codirector of the Tech4Health Institute at NYU Langone Health, and a professor in the ophthalmology and neuroscience departments at the NYU Grossman School of Medicine. "This discovery potentially makes the technique more efficient, lowers the ultrasound power required, and could pave the way to safer transcranial ultrasound stimulation treatments in the future."
To study circuit activation in an intact brain, the researchers needed to hit multiple brain regions with sound waves while also directly monitoring which neurons were becoming activated in the process.
Under the guidance of Shoham and Razansky, the researchers positioned above the mouse's head a helmet-shaped array of 512 ultrasound emitters that was developed by the Swiss team The team created holograms from the ultrasound waves, the same way interfering light waves can create three-dimensional images (like of Princess Leia in the Star Wars films). Sound waves interfering with one another in the right way can also create "images" — in this case, essentially focusing the waves of sound coming from the emitters into defined geometric patterns, such as triangles or pentagons, onto the surface of the brain.
As neurons in the hologram-focused regions became activated, they generated a fluorescence signal that the camera recorded, enabling the researchers to measure to the degree to which different brain regions were activated in response to TUS.
"Our findings provide new insights into how transcranial ultrasound stimulation activates circuits within a living organism," said Shoham. "We hope the techniques and computational models we've developed will help other basic researchers probe the mechanisms of different brain circuits. Ultimately, our goal is to translate this work into transcranial ultrasound stimulation protocols to treat different human conditions, such as mental health disorders."
Moving forward, Shoham said the researchers want to explore activating more complex neural circuits and testing whether they can use ultrasound to activate circuits located more deeply in the brain. Some applications are already being tested in the clinic.
Funding support for this study was provided by National Institutes of Health grants RF1NS126102 and R01NS109885. Additional funding was provided by the Swiss National Science Foundation.
Postdoctoral fellow Théo Lemaire is an NYU Langone co-investigator involved in this study. Other study co-investigators are first author Hector Estrada, Yiming Chen, Neda Davoudi, Ali Özbek and Qendresa Parduzi at the University of Zurich and ETH Zurich.
