A New Device Records Brain Activity from Inside Blood Vessels
The new tool, which was pioneered by a Stanford postdoc, could make it possible to study and treat the brain without causing tissue damage.
Listening in on neurons is a messy business. Sure, a noninvasive scan can get the job done if all you care about is the behavior of big chunks of brain tissue, but tracking the activity of individual neurons in a living animal requires opening up the skull and sticking a metal electrode straight into the tissue. Even if the immediate risks of bleeding and infection are avoided, poking a thin shank of metal into the jelly-like flesh of the brain inevitably kills cells and disrupts delicate neural circuitry.
But there might be another way in. The brain is home to thousands of miles of completely neuron-free passageways: its blood vessels. As far back as the 70s, surgeons snaked recording devices up through the neck and into major arteries and veins in order to record brain activity without harming the neural tissue. The devices were so large, however, that they could only fit into the most capacious blood vessels, and they wouldn’t work at all in small animals like rodents. Turning such endovascular recording into a viable tool for science and medicine required something much, much smaller.
Making a smaller endovascular electrode wasn’t actually all that difficult, says Anqi Zhang, formerly a Ph.D. student in chemistry at Harvard U. and currently a postdoctoral fellow in chemical engineering and bioengineering at Stanford U.: Researchers have worked for years to design miniscule, flexible electrodes that can be implanted directly into the brain. But just having a small electrode wasn’t enough. “The problem is, once you have this device, how do you deliver it into a blood vessel?” she says. The electrodes she initially made when trying to attack this problem were so small and flexible—much less than the size of a single human hair—that they would immediately crumple if threaded into a blood vessel.
Working on her Ph.D. research with Charles Lieber, a retired professor of chemistry and chemical biology at Harvard University, Zhang managed to overcome that challenge. She not only devised a strategy for getting her electrodes into blood vessels—she managed to use them to record the activity of individual neurons, something that had never previously been done with endovascular devices. Her results were recently published in the journal Science.
In trying to figure out how to guide her electrodes into the brain, Zhang looked to long-established procedures for inserting other medical devices into blood vessels. Catheters—flexible, hollow tubes often guided into the vasculature with relatively stiff guidewires—provided a useful analogy. With a guidewire installed, Zhang and her collaborators, Lijun Xu and Emiri T. Mandeville, were able to guide the electrode cleanly into the arteries of a rat’s brain. But she observed something unexpected. Sometimes, the electrode would enter the anterior cerebral artery (ACA), but other times, it would take a different branch and enter the middle cerebral artery (MCA). Even with the help of the guidewire, it was difficult to guarantee where it would end up. Lieber, Zhang’s advisor, presented her with a challenge: Overcome that limitation and contrive a technique for targeting the electrode to a specific blood vessel.
The solution to that challenge ended up being surprisingly straightforward. Because the materials used to make the guidewire and the electrode have different natural curvatures, changing the width of the guidewire changed the angle of the device itself. With a thicker guide wire, the device curves less; with a thinner one, it curves more, video. That observation allowed Zhang to selectively target the sharply branching MCA with a thin guidewire and the more gently deviating ACA with a thick one. This strategy, however, only works to get the device through a single branch point—and in the highly convoluted environment of the brain vasculature, that might not count for much. But Zhang plans to explore other techniques for guiding her electrode, like attaching a magnetic particle to its tip and using external magnets to navigate it to its destination.
Targeting the device to the desired location is one challenge; using it to listen in on neurons is another. Previous endovascular devices had been used to record signals called “local field potentials,” which represent the aggregate activity of large groups of neurons. So that’s what Zhang looked for in her first recordings. But when she examined those recordings, she saw something far more exciting. “When I was doing the recording, I noticed, ‘Oh, there’s actually a single [neuron] recording. That’s really cool!’” she says. Because the rat blood vessels she was targeting were so small, with such thin walls, her electrode was able to get much closer to the neurons than had been possible with previous devices—and that proximity allowed for unprecedentedly precise recording.
Already, Zhang has shown that her device can be used to record from individual rodent neurons without causing any damage to the brain. But she wants her endovascular electrode to see use beyond basic science. The ideal application for the device, she says, is in helping people recover from stroke, which occurs when a blocked blood vessel prevents parts of the brain from receiving oxygen. Electrically stimulating that damaged tissue might help with stroke rehabilitation—and, since that damaged tissue is located near the blocked blood vessel, Zhang’s device might be the perfect way to target it. Granted, Zhang needs to perform more studies to demonstrate that her electrode can be used not only to record from but also to stimulate neurons—but she says she is hopeful. “If it works, if it can impact the neurons outside of the vessels, I think that’s going to be very useful,” she says.
Anqi Zhang is the lead author and conducted this research as a Ph.D. student at Harvard U. She is currently a postdoctoral fellow at Stanford U. Other Stanford co-authors include Creed M. Stary, Associate Professor of Anesthesiology, Perioperative and Pain Medicine (Adult MSD) and, by courtesy, of Ophthalmology; Lijun Xu, M.D., Research Associate and Lab Manager for the Stary Lab. Harvard University co-authors include Emiri T. Mandeville, Instructor of Radiology; Eng H. Lo, Professor of Neurology and Radiology, Massachusetts General Hospital; Charles M. Lieber, retired Harvard Professor of Chemistry and Chemical Biology.
This work was supported through Harvard U. by the Air Force Office of Scientific Research, National Institutes of Health, the Lieber Research Group, the Leducq Foundation, and the American Heart Association. Part of this work was performed at the Harvard University Center for Nanoscale Systems and at the nano@stanford labs, both of which are members of the National Nanotechnology Coordinated Infrastructure Network, which is supported by the National Science Foundation.
The eWEAR-TCCI awards for science writing is a project commissioned by the Wearable Electronics Initiative (eWEAR) at Stanford University and made possible by funding through eWEAR industrial affiliates program member Shanda Group and the Tianqiao and Chrissy Chen Institute (TCCI®).