A Better Way to Probe the Brain
The brain is often described as the most complex structure known: a multitude of cells, joined into networks and abuzz with electrical and chemical activity. As a materials scientist, Polina Anikeeva, PhD ’09, also knows that the brain is far more soft and pliable than the devices we use to study it. “It actually has the elastic properties of chocolate pudding,” says Anikeeva, an assistant professor of materials science and engineering at MIT. “You can spoon it if you want.”
Yet when scientists try to explore the brain, they typically rely on stiff and sharp materials, like silicon probes and steel electrodes. That makes about as much sense, she says, as slicing through pudding with a knife.
With neural implants for humans, such as devices for deep brain stimulation, the mismatch can have severe consequences. Stiff electrodes can cut through tissue if the brain jiggles. Cells from the immune system and nearby tissue swarm in, surrounding any implant with scar tissue. Similar problems apply to neural interfaces for the spinal cord.
Anikeeva, who leads MIT’s Bioelectronics Lab, is developing better ways to interact with the brain and spinal cord. Though her lab is less than four years old, prominent journals have published a string of her group’s papers demonstrating new technologies, including thin, flexible polymer-fiber probes for stimulating and recording activity from neurons, as well as magnetic nanoparticles that could be used to stimulate them with no wires at all. The goal is to probe the brain with a softer touch—and to do so precisely, while integrating several functions into one device.
Anikeeva’s work is already enabling other scientists to perform new kinds of studies on the brain and spinal cord. Ultimately, the materials she creates could offer a less invasive way to connect devices to the human body in order to treat neurological diseases or restore movement.
“I was essentially a science nerd from very early days,” says Anikeeva. She grew up in Saint Petersburg, Russia, the daughter of parents who both trained as mechanical engineers. (Her mother helped design nuclear submarines before the collapse of the Soviet Union.) At 12, she was admitted to the prestigious Physical-Technical High School, which is affiliated with the Ioffe Physical-Technical Institute of the Russian Academy of Sciences. The school has just 180 students and holds classes six days a week; its purpose is to groom future researchers. “It’s harder to get into than it is to get into MIT,” she says.
Anikeeva studied biophysics at the Saint Petersburg State Polytechnic University; on an exchange program at the Swiss Federal Institute of Technology in Zurich, she learned to analyze the structure of proteins using nuclear magnetic resonance spectroscopy. After graduating, she completed a yearlong internship at Los Alamos National Laboratory in New Mexico, designing solar cells from semiconductor nanocrystals known as quantum dots.
When she visited graduate schools, MIT stood out for its students as much as its faculty. “I felt that at MIT I would be surrounded by truly talented people who are fanatical about their work,” she says. She began her doctoral research in 2004 in the lab of Vladimir Bulović, then an associate professor of electrical engineering and computer science, who was developing new electronic and optical devices using nanotechnology. There she pioneered a technique for creating LEDs by using quantum dots to generate light of different colors.
Anikeeva enjoyed working with nanomaterials, but she also had a passion for biology. “We have such sophisticated technologies in our cell phones—we have these beautiful displays, state-of-the-art computing modules, transistors, circuits, and so on,” she says. She wanted to harness some of those advances to improve technology for the body. But “before I would arrogantly go and try to solve problems that I didn’t know existed,” she says, “I decided that I needed to actually spend some time in a biological environment.”
That decision led her to Karl Deisseroth’s neuroscience lab at Stanford University. His group was in the midst of groundbreaking work on optogenetics, which uses light to stimulate cells in animal brains that have been engineered to include light-activated proteins. “When I saw that they were developing methods to control the brain optically, I was really blown away,” she says. It also suggested a new way to apply her skills. “The brain means action potentials and voltages—I figured as an optoelectronics person, I can get behind voltage,” she says. “It’s something that I have some chance of understanding.”
Deisseroth’s group needed hardware to send light into specific areas of mouse brains while also taking electrical recordings from the illuminated cells. During a two-year postdoc beginning in 2009, Anikeeva developed a probe that was more sophisticated than the one they were using; her version included multiple electrodes along the optical fiber. “That was a key step in getting rich readouts back from the fiber-optic interface,” Deisseroth says.
The experience taught Anikeeva how to do experiments and work with animals—and it gave her problems to solve. “Having received this more basic neurobiological training made me think about the tools that we were using,” she says. “Those technologies are really quite primitive. They were too large and too bulky and didn’t have enough capability.” The biologists Anikeeva worked with were manipulating individual wires under microscopes, a far cry from sophisticated fabrication techniques used in the electronics industry.
“I felt that we should be able to do better,” she says. And when she was offered a faculty position at MIT, that premise became the foundation of her own lab. In her current work, Anikeeva is bringing her expertise in materials science to bear on neuroscience. “She’s incredibly talented no matter what she puts her hands on,” says Bulović, now a professor of emerging technology, the School of Engineering’s associate dean for innovation, and co-director of the MIT Innovation Initiative. “She took all these experiences that she acquired … and recognized that she could put them together in a coherent whole.”
A better hammer
In a basement lab at MIT, Andres Canales, SM ’13, a PhD student in Anikeeva’s group, is watching a physical transformation take place: a cylinder of polymers and metal is being slowly melted and pulled into a long, vermicelli-like wire from a tall tower in one corner of the room. One reason Anikeeva was keen to return to MIT was to work with Yoel Fink, the director of the Research Laboratory of Electronics and a leading innovator in this technique of fiber drawing, in which materials are assembled together, heated, and pulled like taffy into ultrathin fibers that preserve the original structure and functionality. Fink has shared with her lab both his expertise and the fiber-spinning tower, which offers precise control and the ability to reduce features to a microscopic level (see Demo).
Thanks to this collaboration, her team has incorporated optical waveguides, electrodes, and drug delivery channels into a single fiber that can be as thin as a human hair and flexible enough to wrap around a finger. And critically, these devices aren’t rejected by the body.
That kind of capability could help neuroscientists trying to untangle complex brain functions in mice. Guoping Feng, a professor of brain and cognitive sciences at MIT’s McGovern Institute, is using Anikeeva’s probes to study psychiatric diseases like autism and obsessive-compulsive disorder. His work involves looking at the communication among neurons in the brain and the relationship between genes, brain circuits, and behavior. To observe these processes in living animals, researchers must be able to manipulate specific circuits precisely and record activity from the manipulated cells. With a thin, multifunctional device, he says, “you can have all the capability with minimal perturbation or damage to the brain tissues.”
The devices can also be used in the spinal cord, which is challenging to access and requires a flexible device because it is often moving and stretching. Although electrical stimulation of the spinal cord can evoke movement in paralyzed animals and has been used clinically in humans with modest results, Chet Moritz, a professor of rehabilitation medicine at the University of Washington in Seattle, says that optical stimulation could allow more precise control of specific cells. “Electrical stimulation is a fairly large hammer,” he says. “With optogenetics, you can have fairly high confidence that you are activating a specific circuit.”
Moritz works on stimulating the upper spinal cord—ultimately in order to restore movements like reaching and grasping, which require more finesse than walking. To do that, he needs to target specific neurons directly. Working with Anikeeva, he’s testing the feasibility of using light to stimulate the spinal cords of rats with an eye toward reanimating paralyzed limbs.
Wireless brain stimulation
Meanwhile, Anikeeva is pursuing technologies that can stimulate specific brain areas with no wires at all. In a recent paper in , her group demonstrated a technique that uses magnetic fields and injected nanoparticles to activate cells deep within the brains of mice.
In this process, magnetic nanoparticles are heated with the help of alternating magnetic fields, which pass easily through brain tissue without affecting it. For decades, researchers have been working on techniques for injecting magnetic nanoparticles into tumors and heating them with magnets to kill the cancerous cells. But rather than destroying cells, Anikeeva wanted to create a quick burst of heat that would make neurons fire.
Other scientists have used a similar approach to stimulate cells engineered to express the heat-responsive protein TRPV1. But Anikeeva says the cells in these studies responded too slowly for the kind of immediate stimulation she wants to achieve.
Her team, led by graduate students Ritchie Chen, SM ’13, and Michael Christiansen, started modeling how magnetic nanoparticles dissipate heat. The particles align themselves to a magnetic field and realign when its direction changes, releasing heat in the process. The models showed that this effect was more potent if the size and shape of the particles matched the properties of the magnetic field. By tailoring the design of both the magnetic coils and the nanoparticles, the researchers were able to produce more heat faster.
The particles are made from iron oxide (commonly used as a contrast agent in MRIs) and coated in polymers to keep the body’s immune system from whisking them away. Anikeeva’s team used a virus to deliver the gene for TRPV1 into cells in a specific part of the brains of mice. Then they injected the same region with the nanoparticles. Under the magnetic field, the particles heated up, causing the modified neurons to fire.
Anikeeva is now investigating whether varying the magnetic fields and the composition of the particles can make it possible to target multiple cell types or brain circuits. And while this study used genetic engineering to get a heat-sensitive protein into mouse cells, she says that TRPV1 is prevalent in the human brain, so such tinkering may not be necessary to use the technique in humans.
This demonstration, preliminary though it is, points toward a much less invasive way of stimulating cells deep within the brain. Currently, patients who get deep brain stimulation for conditions like Parkinson’s disease need surgery to implant electrodes wired to an external battery. These mice had a simple injection, and the magnetic nanoparticles remained active a month later. One day, she imagines, patients could receive a magnetic drug and spend a prescribed amount of time each day near a magnetic device.
Anikeeva’s group is refining these technologies and seeking collaborators who will put them to the test. She envisions using soft polymer probes to precisely map the brain, or to deliver a drug or optical stimulation and then monitor its effect on cell activity.
She’s also keenly interested in using the technologies as neural interfaces to treat paralyzing injuries. When a friend suffered a serious spinal-cord injury while rock climbing, Anikeeva was struck by the primitive state of technology for rehabilitation and restoring movement. “It influenced my research program in very profound ways,” she says.
An enthusiastic rock climber and distance runner herself, Anikeeva is especially interested in movement because she finds it essential to her own thinking. “Climbing is a big, defining part of my life,” she says, and she often works out problems while running for two or three hours at a time. “I never exercise with music,” she says. “Essentially it’s me against my brain.”
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