Small magnetic disks provide remote brain stimulation without transgenes

New magnetic nanodisks could offer a much less invasive way to stimulate parts of the brain, paving the way for stimulation therapies without implants or genetic modification, MIT researchers report.

The scientists envision that the tiny disks, which are about 250 nanometers wide (about 1/500 the width of a human hair), would be injected directly into the brain at the desired location. From there, they can be activated at any time by simply applying a magnetic field outside the body. The new particles could quickly find applications in biomedical research and eventually, after sufficient testing, be applied to clinical applications.

The development of these nanoparticles is described in the journal Nature Nanotechnologyin an article by Polina Anikeeva, professor in MIT’s Departments of Materials Science and Engineering and Brain and Cognitive Sciences, graduate student Ye Ji Kim, and 17 others at MIT and in Germany.

Deep brain stimulation (DBS) is a common clinical procedure in which electrodes are implanted into target brain areas to treat symptoms of neurological and psychiatric disorders such as Parkinson’s disease and obsessive-compulsive disorder. Despite its efficacy, the surgical problems and clinical complications associated with DBS limit the number of cases in which such an invasive procedure is warranted. The new nanodisks could offer a much friendlier way to achieve the same results.

Over the past decade, other implant-free methods of producing brain stimulation have been developed. However, these approaches were often limited by their spatial resolution or ability to target deep areas. Over the past decade, Anikeeva’s Bioelectronics group and others in the field have used magnetic nanomaterials to remotely convert magnetic signals into brain stimulation. However, these magnetic methods relied on genetic modifications and cannot be used in humans.

Because all nerve cells are sensitive to electrical signals, Kim, a graduate student in Anikeeva’s group, hypothesized that a magnetoelectric nanomaterial that can efficiently convert magnetization into electrical potential could provide a path to remote magnetic brain stimulation. However, creating a nanoscale magnetoelectric material was a huge challenge.

Kim synthesized new magnetoelectric nanodisks and worked with Noah Kent, a postdoc in Anikeeva’s lab with a background in physics and a second author on the study, to understand the properties of these particles.

The structure of the new nanodisks consists of a two-layer magnetic core and a piezoelectric shell. The magnetic core is magnetostrictive, meaning it changes shape when magnetized. This deformation then causes stress in the piezoelectric shell, creating varying electrical polarization. The combination of the two effects allows these composite particles to deliver electrical pulses to neurons when exposed to magnetic fields.

A key to the effectiveness of the discs is their disc shape. Previous attempts to use magnetic nanoparticles had used spherical particles, but the magnetoelectric effect was very weak, Kim says. This anisotropy enhances magnetostriction by more than a thousandfold, Kent adds.

The team first added their nanodisks to cultured neurons, which then allowed these cells to be activated on demand with short pulses of a magnetic field. No genetic modification was required for this stimulation.

They then injected small droplets of magnetoelectric nanodisc solution into specific parts of the mice’s brains. Then, simply turning on a relatively weak electromagnet nearby caused the particles to release a small jolt of electricity in that brain region. The stimulation can be turned on and off remotely by switching the electromagnet. That electrical stimulation “had an impact on neuron activity and behavior,” says Kim.

The team found that the magnetoelectric nanodiscs could stimulate a deep brain region called the ventral tegmental area, which is associated with feelings of reward.

The team also stimulated another brain region, the subthalamic nucleus, which is linked to motor control. “This is the area where electrodes are normally implanted to treat Parkinson’s disease,” Kim explains. The researchers were able to successfully demonstrate the modulation of motor control via the particles. By injecting nanodisks into only one hemisphere, the researchers were able to induce rotations in healthy mice by applying a magnetic field.

The nanodisks could induce neuronal activity comparable to conventional implanted electrodes that deliver mild electrical stimulation. The authors achieved sub-second temporal accuracy for neural stimulation with their method, but observed a significantly reduced foreign body response compared to the electrodes, potentially allowing for even safer deep brain stimulation.

The multilayer chemical composition and physical shape and size of the new multilayer nanodisks have enabled precise stimulation.

Although the researchers have successfully increased the magnetostrictive effect, the second part of the process, converting the magnetic effect into an electrical output, still requires more work, Anikeeva says. While the magnetic response was a thousand times greater, the conversion into an electrical impulse was only four times greater than with conventional spherical particles.

“This huge improvement of a thousandfold did not fully translate into a magnetoelectric improvement,” says Kim. “That’s what a lot of the future work will be focused on, to ensure that the thousand-fold gain in magnetostriction can be converted into thousand-fold gain in the magnetoelectric coupling.”

What the team discovered, in terms of how the particles’ shapes affect their magnetostriction, was quite unexpected. “It’s something new that just appeared when we were trying to figure out why these particles worked so well,” says Kent.

Anikeeva adds: “Yes, it is a record-breaking particle, but it is not as record-breaking as it could be.” That remains a topic for further work, but the team has ideas on how further progress can be made.

Although these nanodiscs could in principle already be applied to basic research using animal models, a number of steps would still be needed to translate them to clinical use in humans, including large-scale safety studies. to do,” says Anikeeva. “If we find that these particles are really useful in a particular clinical context, we imagine there will be a path for them to undergo more rigorous safety studies in large animals.”

The team included researchers from MIT’s Materials Science and Engineering, Electrical Engineering, and Computer Science, Chemistry, and Brain and Cognitive Sciences departments; the Electronics Research Laboratory; the McGovern Institute for Brain Research; and the Koch Institute for Integrative Cancer Research; and from the Friedrich-Alexander University of Erlangen, Germany. The work was supported in part by the National Institutes of Health, the National Center for Complementary and Integrative Health, the National Institute for Neurological Disorders and Stroke, the McGovern Institute for Brain Research, and the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics in Neuroscience.