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March 31, 2020

Cleaning the brain: Study shows electric stimulation affects clearance

Written By: Tom Ziemer


By using an implanted device to electrically stimulate the vagus nerve, doctors can treat patients for epilepsy, depression and a growing number of other conditions.

But it turns out those electric pulses affect the brain’s clearance systems—which may explain their therapeutic effectiveness and could open the door for a new way to treat neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

 Kip Ludwig
Kip Ludwig

In a paper published online in the journal Brain Stimulation, a team of researchers led by University of Wisconsin-Madison biomedical engineers Kip Ludwig and Justin Williams demonstrated that stimulating the cervical vagus nerve in the neck increased the penetration of cerebrospinal fluid in the brain. That’s evidence, the authors note, of an increased flow of fluid through the brain’s clearance systems, carrying with it waste products and misfolded proteins.

Those misfolded proteins, of course, are known to collect and strangle off neurons in a host of neurodegenerative diseases.

“It’s a completely new paradigm that might explain existing vagus nerve stimulation effects for epilepsy and depression, but it’s also a completely untapped mechanism,” says Ludwig, an associate professor of biomedical engineering and neurological surgery. “The hope is that we can start looking at hijacking the nervous system to prevent diseases like Alzheimer’s and Parkinson’s from ever occurring.”

The researchers used a fluorescent tracer to track the cerebrospinal fluid (CSF) of mice that were stimulated with an implanted cervical vagus nerve cuff. The fluid moves through the brain’s glymphatic system, one of two complementary clearance systems discovered by researchers since 2012 that are believed to play crucial roles in maintaining homeostasis in our brains.

“In that system, you can imagine sort of a pipeline,” says Kevin Cheng (PhDBME ’16), an assistant scientist in the Department of Biomedical Engineering and co-first author on the paper along with assistant researcher Sarah Brodnick. “You have CSF flowing into the brain, and as it flows in, it collects extracellular molecules like toxic byproducts, metabolic byproducts, and then flushes that out toward the paravenous drainage. So by measuring CSF entering, we are, in effect, measuring that flow.”

By employing an implanted cuff electrode and stimulation parameters—length, intensity and frequency—that are both already approved for clinical use by the U.S. Food and Drug Administration, Ludwig says the group can now quickly move on to imaging brains of patients to confirm the effect in humans.

“We can literally go test this in the clinic in the next year,” says Ludwig, who is also the neuroengineering lead for UW-Madison’s Grainger Institute for Engineering.

Ultimately, Ludwig aims to connect the research to his group’s work on an injectable electrode—the “injectrode”—to explore potential preventative treatments for neurodegenerative diseases through minimally invasive means.

“What we’re trying to do is create something that we can do before all these proteins have aggregated into plaques,” he says. “But to do that, we need to get to something that can be really minimally invasive. If you’re going to do it to prevent someone from ever getting Alzheimer’s disease or Parkinson’s disease, you need to get to something that’s trivially invasive.”

This research was funded through the Targeted Neuroplasticity Training program in the Defense Advanced Research Projects Agency’s Biological Technologies Office. Other UW-Madison authors include Stephan Blanz, Jack Kegel, Jane Pisaniello, Jared Ness, Evan Nicolai, Megan Settell and James Trevathan from the Department of Biomedical Engineering; Samuel Poore from the Department of Biomedical Engineering and the Department of Surgery in the School of Medicine and Public Health; Aaron Suminski from the Department of Biomedical Engineering and the Department of Neurological Surgery in the School of Medicine and Public Health; and Weifeng Zeng from the Department of Surgery. Mayo Clinic also collaborated on the work.