The BRAIN Initiative: Changing Neuroscience

Science is changing. Before the second half of the 20^th Century, many scientists worked alone or in small, one-site teams to advance their fields of study. Now, research teams commonly consist of several labs in different disciplines and pursuing multiple lines of inquiry. This interconnectivity has dramatically accelerated scientific discovery, as scientists whose work may have previously been isolated are able to pool resources, share research, and draw from one another’s expertise. But what forces are driving these changes in the practice of science?

Pesaran’s lab studies how groups of neurons communicate across the brain to guide behavior in nonhuman primates

One force is the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, a large-scale, public-private research program first funded in 2014. It aims to revolutionize our understanding of the human brain, the most complex structure in the known universe. To pursue its bold goal, the initiative is tailoring the questions it asks — and the funding it provides — to support changes in the practice of science that may speed up and strengthen discovery.

From grant writing to data sharing, the many ways in which the BRAIN Initiative has encouraged brain science to evolve are evident.

“The BRAIN Initiative has been influential conceptually and methodologically,” says New York University’s Bijan Pesaran. Pesaran’s lab studies how groups of neurons communicate across the brain to guide behavior in nonhuman primates, applying what is learned about brain networks to develop new technologies for clinical use in humans.

One transformation spurred by the BRAIN Initiative is in the scope of neuroscience research projects.

“The Initiative has encouraged us to extend the scope of our work from pairs of regions talking to each other to more complex networks,” says Pesaran. “It has given us the tools to study communication across the brain and model it with computational models. We’re now working with concepts about how brain networks behave that we could not have even discussed five years ago.”

Hongkui Zeng, the executive director of Structured Science at the Allen Institute for Brain Science.

Hongkui Zeng, the executive director of Structured Science at the Allen Institute for Brain Science, also says the BRAIN Initiative has strengthened and expanded the scope of her research program.

“We were originally only able to ask our questions in one or a couple brain regions,” she says. “Now we are able to systematically characterize cellular diversity across many different cortical and subcortical regions of the brain. We have a much more comprehensive view and understanding of the organizational rules of the brain.”

The BRAIN Initiative has influenced the scope of research programs through its use of somewhat unique funding mechanisms. One type of NIH BRAIN Initiative funding are U grants, known as cooperative agreements. According to Andrea Beckel-Mitchener, the acting director of the Office for Disparities Research and Workforce Diversity and the Office of Rural Mental Health Research, U grants encourage cross-pollination between researchers.

“U19s, for instance, are complex multi-project grants with many components,” says Beckel-Mitchener. “Whereas individual projects might be funded with an R01, having a U19 mechanism makes it easier to manage multiple projects that are working on similar questions. You maximize the reach of these individual projects by having them work together in a more coordinated way.”

One such large collaboration is the BRAIN Initiative Cell Census Network (BICCN), launched in 2017 with the goal of constructing a comprehensive reference of diverse cell types in human, monkey, and mouse brains. Within the network, individuals with U grants operate somewhat independently on their own projects. But they also communicate regularly and come together several times a year to coordinate their activities and maximize progress as well as avoid research duplication.

“They learn from one another,” says Beckel-Mitchener. “It amps up the ability of these projects to get things done.”

Pesaran says that unlike more traditional R01-funded research, which requires a well-defined approach and set of outcomes that one can interpret, the BRAIN Initiative's funding mechanisms emphasize innovation and significance more than approach and preliminary data.

"The funding has allowed us to develop concepts that we were unlikely to think about before,” he says.

Tianyi Mao of Oregon Health and Science University also says the Initiative’s funding mechanisms have influenced her research. Her lab develops new imaging approaches that allow direct observation of events within individual brain cells in living animals. They aim to apply these tools to investigate the brain circuit mechanisms underlying a variety of behaviors.

“I didn’t have much preliminary data, but I did have previous qualifications, a clear strategy, and a good collaborator,” which was enough to secure funding from the program, says Mao. “A traditional R01 would require that I show the feasibility before they give me money to improve it. I wouldn’t be able to do this type of research based on traditional grant mechanisms. The results obtained through the Initiative grants demonstrated the feasibility of some risky strategies which in turn allows us to apply for traditional funding mechanisms.”

Another way the BRAIN Initiative is changing neuroscience is by encouraging collaborations, particularly interdisciplinary ones. Collaborations of researchers from various disciplines, including computer science, engineering, physics, and chemistry, will be essential to the advancement of neurotechnology.

“The BRAIN Initiative has really promoted these collaborations and accelerated the ability of different people to come together to work on significant neuroscience questions,” says Beckel-Mitchener. “Different types of investigators are collaborating more freely and seamlessly than they were in the past and that moves the science forward faster.”

Mao says one of her BRAIN Initiative grants has three principal investigators, all doing complementary work.

“That’s the strength of the BRAIN Initiative: encouraging collaboration that you might otherwise not have,” she says.

Zeng agrees. “Some technologies we had not adopted at the Allen Institute, but now we are working together with collaborators and able to compare our data with data coming out of different technologies,” she says. “This gives all of us an opportunity to tackle the problem more effectively from different perspectives.”

Bruce Tromberg, director of the National Institute of Biomedical Imaging and Bioengineering, says that the BRAIN Initiative is stimulating a tremendous amount of activity in the technology development space and bringing new people into the neuroscience community. “The Initiative has enriched the neuroscience community and the technology development community. It’s been a great two-way street.”

Tromberg says that people’s inherent inquisitiveness about the brain is a powerful draw for scientists from other disciplines. Multidisciplinary teams are pushing the envelope in new methods in computational neuroscience and neuroimaging.

“New resources from the BRAIN Initiative have given neuroscientists opportunities to introduce cutting-edge methods into neuroscience, often with technologies that developers may not have intended for neuro applications,” says Tromberg.

Large-scale efforts such as the BICCN generate extraordinary amounts of data to be stored and analyzed. These data are acquired in a standardized manner to enable sharing among the participating labs.

“We are required by NIH to deposit our data, pre-publication, to a common repository and make them publicly available periodically,” says Zeng. “We can compare our data with complementary data from different labs in a highly collaborative manner. It accelerates discovery.”

Mao also believes that data sharing and dissemination is a major emphasis of the BRAIN Initiative.

“They have been very supportive of our plan to share openly with the public, to do it in the best format, and to do it with long-term impact in mind,” she says. “That’s a mentality change.”

Beckel-Mitchener adds, “It is about supporting new science and technologies that will help mold brain research into the 21^st century and beyond."

The value of the BRAIN Initiative extends beyond the tools and techniques generated for neuroscientists. Successful new practices that speed up and strengthen discovery can be shared broadly with other disciplines, and shortening the timeline from discovery to treatment will benefit countless patients living with Alzheimer’s disease, autism, and many other brain disorders.

As neuroscience delves into larger, ever-more complex challenges, the BRAIN Initiative and other international brain projects are encouraging the field to evolve its methods to accelerate discovery.