Deep brain stimulation, which now involves surgically inserting electrodes several inches into a person's brain and connecting them to a power source outside the skull, can be an extremely effective treatment for disorders such as Parkinson's disease, obsessive compulsive disorder, and depression. The expensive, invasive procedure doesn't always work, however, and can be risky.
Now, a study in mice points to a less invasive way to massage neuronal activity, by injecting metal nanoparticles into the brain and controlling them with magnetic fields. Major technical challenges must be overcome before the approach can be tested in humans, but the technique could eventually provide a wireless, nonsurgical alternative to traditional deep brain stimulation surgery, researchers say.
"The approach is very innovative and clever," says Antonio Sastre, a program director in the Division of Applied Science & Technology at the National Institute of Biomedical Imaging and Bioengineering in Bethesda, Maryland. The new work provides "a proof of principle."
The inspiration to use magnets to control brain activity in mice first struck materials scientist Polina Anikeeva while working in the lab of neuroscientist-engineer Karl Deisseroth at Stanford University in Palo Alto, California. At the time, Deisseroth and colleagues were refining optogenetics, a tool that can switch specific ensembles of neurons on and off in animals with beams of light.
Optogenetics has revolutionized how neuroscientists study the brain by allowing them to directly manipulate specific neural circuits. But it isn’t practical for human deep brain stimulation. The technique requires that animals be genetically modified so that their neurons respond to light. Light also scatters in brain tissue. So rodents in optogenetics experiments must remain tethered to a surgically implanted, fiber optic cable that delivers laser beams directly to the brain region of interest.
Unlike light, low-frequency magnetic fields pass straight through brain tissue as if it were "transparent," Anikeeva says. That makes those types of magnetic fields an ideal vehicle for delivering energy into the brain without damaging it. Clinicians have long tried to do just that by placing magnetic field coils near a patient’s head. This so-called transcranial magnetic stimulation (TMS) triggers the flow of small electrical currents in neural circuits beneath the coils. But the magnetic fields used in TMS affect only brain tissue near the brain’s surface. Anikeeva, who is now at the Massachusetts Institute of Technology (MIT) in Cambridge, decided to see if she could use magnetic nanoparticles to go deeper.
Previous cancer studies had shown that by injecting tumors with magnetic nanoparticles made of iron oxide—“essentially rust, with well-tuned magnetic properties," Anikeeva says—then exposing them to rapidly alternating magnetic fields, excited nanoparticles can be used to heat and destroy cancer tumors while leaving surrounding, healthy tissue intact. Anikeeva wondered if a similar method could be used to merely stimulate select groups of neurons deep within the brain.
To find out, she and her MIT colleagues targeted a class of proteins called TRPV1 channels, which are found in neurons that respond to heat and certain chemicals in food. Every time you touch a hot iron or eat a spicy pepper, TRPV1-containing neurons fire. Anikeeva and her colleagues injected custom-made, 20-nanometer iron oxide particles into a region of the rodents' brains called the ventral tegmental area (VTA), a well-studied deep brain structure essential to the experience of reward, which plays a central role in disorders such as addiction and depression in people.
TRPV1-containing neurons are abundant in this region in humans, but sparse in mice. So the team also injected the rodents with a virus that increased cell expression of the channel just within that brain area. Such an approach would not be feasible in people, but made the experiment easier to evaluate, Anikeeva says.
A few days later, the team put the mice underneath a custom-built, 6.35-centimeter-diameter coil that emits magnetic waves alternating between 10 hertz and 10 millihertz. Hours after the team applied the magnetic fields, they sacrificed the animals and examined their brain tissue under a microscope. The mice were a strain previously engineered to produce a bright green fluorescent marker in any active neurons. A large network of neurons connected to the VTA glowed green, suggesting that the magnetic fields had effectively stimulated the circuit, the team reports online today in Science. Anikeeva and colleagues found similar results when they waited a month before applying the magnetic stimulation, suggesting that the nanoparticles endured in place.
To make the approach feasible in humans, researchers need to design nanoparticles that are "very, very selective" in their ability to target specific brain structures and neurons, Sastre says. TRPV1 channels are widely distributed throughout the human brain, so another major challenge is figuring out how to deliver stimulation only to the cells researchers want to target, he adds.
In a “perfect, futuristic picture,” Anikeeva says, people suffering from depression or other neurologic or psychiatric disorders could come in for a simple intravenous injection of finely tuned, targeted nanoparticles that reach the region of the brain needing stimulation. In theory, such stimulation could take place every time patients go to sleep, if the magnetic coil were installed in their bed or a specialized pillow, she suggests. For now, however, the technique is most promising as a potential method of studying brain activity in animals that allows them to roam their enclosures without being tethered to wires, she says. “We’re not necessarily thinking of a clinical perspective yet," Anikeeva emphasizes.
(Video credit: Ritchie Chen and Polina Anikeeva)