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New Research Offers Minimally Invasive Approach to Deep Brain Stimulation

Viviana Gradinaru
Viviana Gradinaru hopes her work will overcome hurdles associated with existing treatments for brain disorders. | Photo courtesy of Vilcek Foundation

For her work on strategies that enable precise, minimally invasive alteration of nerves, Viviana Gradinaru is the 2020 grand prize winner of the Science & PINS Prize for Neuromodulation. Her work opens up the potential for noninvasively reaching targets deep in the brain, to treat brain disorders. Its application in a mouse model of Parkinson's disease shows it could be a way to treat brain disorders by targeting the nervous system outside the brain and spinal column, sometimes called the peripheral nervous system.

By moving beyond the brain-centric strategies commonly applied in neuroscience, the approaches Gradinaru developed may help overcome hurdles associated with existing treatments for brain disorders — many of which have failed to pass clinical trials.

"I hope our work … as well as methods for anatomical and functional mapping of the peripheral nervous system and its relevance for central nervous system dysfunction can inform earlier intervention points and approaches to therapies," said Gradinaru, professor of neuroscience and biological engineering at the California Institute of Technology.

Despite the wealth and quality of basic neuroscience research, brain disorders remain some of the hardest diseases to diagnose or treat in the United States. Based on population projections from the U.S. Census Bureau, over 1.2 million people will have Parkinson's disease by 2030. The National Institute of Aging reports that Lewy body dementia — a hard-to-diagnose condition appearing in individuals 50 years or older — affects more than one million people in the U.S. According to the National Institutes of Health, 2 to 5 out of every 100,000 people in the nation suffer from multiple system atrophy, a brain disorder that affects movement and balance.

In recent years, Gradinaru has studied how deep brain stimulation via optogenetics — which uses light to control neurons that have been genetically modified — can treat brain disorders. Her work has revealed that researchers need to be able to access relevant cell populations with less invasive, more precise tools — including those that could penetrate the blood-brain barrier protecting the adult brain. This would allow genetic modifications to be delivered without surgery and invasive intracranial injections. Those seeking to fully understand brain diseases also need to intervene earlier, which would require them to look beyond the central nervous system.

In 2016, Gradinaru led the development of a novel tool called "CREATE" that allowed scientists to deliver adeno-associated viral vectors, harmless viruses that most people carry, across the blood-brain barriers of adult mice. As described in her prize-winning essay, she and her colleagues sought to improve the light-sensitive nature of the opsin proteins delivered by AAVs designed to treat brain disease. In doing so, they developed opsins with "exceptional" light sensitivity. Tested in mice, the opsins worked when the light sources used to direct them were placed on a skull, rather than implanted directly in the brain via optical fibers, the more traditional and invasive route.

Gradinaru paired engineered vectors with designer opsins selected by machine learning for their unprecedented light sensitivity, which allowed the vectors to penetrate large tissue volumes in the brains of mice.

Gradinaru and her colleagues hypothesized they could use their approach to target non-neuronal brain cells that have recently been thought to contribute to brain disorders, including those in the peripheral nervous system and those that lead to a compromised blood-brain barrier.

A test in the nervous systems in the guts of mice showed the approach could signal the peripheral nervous system to reduce the production of amyloid α-synuclein fibrils, proteins that are known to drive brain disorders. This reduced Parkinson's-associated symptoms in the mice. Targeting the gut nervous system in this way may serve as a promising future route for treating Parkinson's disease, said Gradinaru.

"The development of minimally invasive gene delivery tools and identification of novel therapeutic targets in and outside the brain can increase the accessibility and effectiveness of neuromodulation," said Science Translational Medicine editors Mattia Maroso and Caitlin Czajka.

Since 2016, the Science & PINS Prize for Neuromodulation annually honors scientists for excellent contributions to neuromodulation research with implications for translational medicine. The winner of the Science & PINS Prize for Neuromodulation is awarded US$25,000 and publication of his or her essay in Science.

"Neuromodulation is a very promising field," said Chong Li, CEO of PINS Medical, who noted that the prize is the first and the only special academic award in neuromodulation globally. "Neuromodulation not only provides patients with new treatment options and possibilities, but also promotes collaborative research by experts in different academic areas."


Guosong Hong
Guosong Hong

Guosong Hong is the 2020 finalist for his essay "Seeing the Sound." Hong received his undergraduate degree from Peking University and a Ph.D. from Stanford University. After completing his postdoctoral fellowship at Harvard University, Hong started his lab in the Department of Materials Science and Engineering at Stanford University in 2018. His research aims to develop new materials-enabled neurotechnologies to interrogate and manipulate the brain with high spatiotemporal resolution, minimal invasiveness and targeted neural specificity.




[Credit for associated image: MIT]