New soft implantable probe can track fluctuations in brain chemicals

A new string-like implant can track fluctuations in brain chemicals, like a brain fitness tracker.

Imbalances in brain chemistry are at the heart of many neurological diseases. These same brain chemicals also play a role in gut health. So Stanford scientists invented “NeuroString”: a soft implantable probe that can communicate seamlessly with both brain and intestinal tissue. They describe the probe in a paper published on June 2, 2022 in Nature† It has potential applications in depression, Parkinson’s disease and bowel disease.

The main way people try to understand the brain is by reading and recording electrical signals. But chemical signals play an equally important role in brain communication and are also directly related to disease.”

Jinxing Li, the newspaper’s first author

Li started and performed the work as a postdoctoral fellow in Zhenan Bao’s lab in Stanford’s Department of Chemical Engineering; he is now an assistant professor of biomedical engineering at Michigan State University.

NeuroString measures dopamine and serotonin, two chemical messengers that modulate electrical signals in neurons. Dopamine is best known for its role in the brain’s reward system; Serotonin is the target of antidepressants such as Prozac. Both are also involved in exercise, sleep, appetite and digestion.

Implants that measure dopamine and serotonin already exist, but they are made of rigid carbon rods encased in glass tubes. “Those are very stiff probes, they’re very brittle,” says Li. Not only can the implant shatter, it also rubs against the squishy tissue in the brain, which can inflame brain cells and damage the implant.

Bao’s lab has developed a soft probe. “My group has been making soft electronics for quite some time now,” said Bao, the KK Lee Professor and chair of the Chemical Engineering Department at the Stanford School of Engineering. The probe is made of graphene, a form of carbon that is atomically thin. Bao’s team used a laser to engrave what Li describes as a “hairy entangled network of graphene” into a plastic. The plastic contains molecules that turn into nanoparticle dots on the graphene surface that may improve sensitivity and selectivity for simultaneous measurement of dopamine and serotonin. They then embedded the network in a rubber matrix. “Graphene itself isn’t very stretchy, but when it’s entangled like a mesh and embedded in a rubber, it becomes stretchy,” explains Li.

Bao adds: “It’s like a kirigami. If you cut patterns in it and then you can stretch it, you see a kind of hollow bonded paper mesh. It’s the same here, but the mesh is made of graphene sheets.” NeuroString has the same softness as biological tissue. “The sensor is soft and elastic, like a rubber band, which causes no damage when implanted in the brain or gut, which is not only soft but also constantly in motion,” Bao says.

To test the probe, Bao’s team collaborated with Stanford scientists from biology, psychiatry, gastroenterology and surgery. “I think that’s the most privileged part of Stanford: it’s quite open and collaborative,” Li says. The work was supported by a Bio-X seed grant and a Wu Tsai Neurosciences Institute Big Ideas in Neuroscience grant, both of which encourage interdisciplinary collaborations.

In one experiment, the team implanted NeuroString in the brains and gut of the same mice. When they fed the mice chocolate syrup, NeuroString detected spikes of dopamine in the brain and spikes of serotonin in the gut — both expected responses to chocolate. Dopamine is made in the brain, while serotonin is mostly made in the gut. In another experiment, NeuroString detected distinctive patterns of gut serotonin in mice with gut inflammation compared to healthy mice.

“The first time we saw the probe’s signal was a eureka moment,” said study co-author Xiaoke Chen, an associate professor of biology. “Chronic recording of dopamine and serotonin signals in freely moving animals is a dream experiment that we have always wanted to do. And with this beautiful collaboration we were able to make it come true.”

The implanted mice behaved and ate normally and had normal bowel movements. “The exciting thing about the tool was that it didn’t seem to interfere with normal tissue function,” said study co-author Aida Habtezion, a professor of medicine. This means the implant could one day be used for real-time monitoring in humans, similar to a smartwatch but capable of tracking biochemical levels rather than heart rate or steps, she says. Habtezion is currently on leave and serves as Pfizer’s Chief Medical Officer, but contributed to the work when she was still at Stanford.

Tracking serotonin levels in the gut can be helpful in diagnosing and monitoring gut diseases such as irritable bowel syndrome. Monitoring dopamine levels in the brain can be helpful in Parkinson’s disease, which is caused by a deficiency of dopamine. One of the treatments for Parkinson’s disease, deep brain stimulation, works in part by stimulating neurons to produce more dopamine. If deep brain stimulators could be combined with NeuroString, doctors could closely monitor the amount of dopamine released.

The implant is not yet ready for clinical use. For starters, the probe is still attached to wires that read the signals; a wireless version would be needed for use in humans. Meanwhile, the probe has many applications in research. For example, antidepressants like Prozac work by modulating serotonin levels, which may explain why they sometimes cause gastrointestinal side effects, Chen says. “We now have the tool to enable real-time monitoring of the impact of those drugs on serotonin fluctuation in both the brain and gut in mouse models.”

He adds, “Now that we’ve shown that the probe works, there’s a very long list of biological questions that we want to address.”


Reference magazine:

Li, J., et al. (2022) A tissue-like neurotransmitter sensor for the brain and gut. Nature

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