Five years ago, a cooperative multidisciplinary team of researchers at the University of Pittsburgh (Pitt) and its medical center set out to tackle an important translational research goal: Restoring function for those who can’t move. Now, for the first time, breakthrough brain-computer-interface research published in the Lancet in December 2012 provides hope to nearly 6 million paralyzed individuals and another 1.7 million amputees nationwide.
The collaboration relied on help from four federal agencies ― NIH, the Department of Defense (DoD), the Department of Veterans Affairs (VA), and the U.S. Food and Drug Administration (FDA) ― along with support by a private foundation, two academic research centers and a private company. Supporting such teams to overcome roadblocks in the translational research process and turn basic discoveries into tangible health improvements is exactly what NCATS strives to accomplish.
"The problems don’t end when you build a robotic arm or better computer-access," explained Michael Boninger, M.D., professor and chair of the Department of Physical Medicine and Rehabilitation in the Pitt School of Medicine. "The problem has always been how someone with limited ability can control the device." Boninger and his co-investigator, Andrew B. Schwartz, Ph.D., a Pitt neuroscientist, agreed: "If we could get the technology into humans, we could have them playing the piano," he recalled saying to Boninger at the start of the project. It was with this patient perspective in mind that the team set out to make the technology work.
From the beginning, it was made possible by the Pitt Clinical and Translational Science Institute (CTSI), supported by NCATS' Clinical and Translational Science Awards (CTSA) program. "There is a really collaborative group of researchers at Pitt. It's a critical mass," said Boninger. "And then there’s the structure that supported all of that: the CTSI."
The Pitt CTSI, which is one of about 60 CTSA-funded academic research centers dedicated to strengthening the entire spectrum of translational research, facilitated this work by providing training, regulatory expertise and pilot research support.
Turning a Possibility into a Reality
As explained in the Lancet study, the Pitt team implanted electrodes into a paralyzed patient’s brain so they could pick up her brain signals while she imagined moving her hand and arm. A computer interface translates the signals, allowing her to control with her mind the prosthetic arm and hand in a full range of motion, including the ability to grasp objects.
The Pitt CTSI paved the road to this accomplishment by providing initial research funding and helping to assemble the diverse team required. In 2007, bioengineer Wei Wang, M.D., Ph.D., joined Boninger's department. Wang’s previous research helped discover changes in brain signals when people moved their fingers and hands in different directions. Wanting to use this insight to help paralyzed patients, Wang met with his new colleagues at Pitt to discuss ways to push the work forward. Representatives of the CTSI and the head of the Pitt Institutional Review Board (IRB) Office were in attendance to help expedite the translation of this idea into the clinic.
"From the very beginning, our stated goal was a clinical trial," Elizabeth Tyler-Kabara, M.D., Ph.D., remembered.
The Pitt CTSI awarded a Translational Tool Pilot Project grant to Wang and his new research partner, neurosurgeon Tyler-Kabara. The grant required a multidisciplinary team approach, formalizing the existing collaboration between neurologists, neurosurgeons, neurobiologists, bioengineers and physicians.
On the Road to Translation
Using a surgically implanted micro-electrocorticography (ECoG) electrode grid, the team began by mapping the association between brain waves and arm and hand movement in patients already scheduled for epileptic seizure monitoring. Once they had mapped the signals, the team programmed a computer to interpret the results and convert them into movement in computer games. The volunteer epilepsy patients soon were able to use their thoughts to control movement of a cursor or an animation character on a computer screen.
Funding from NIH’s National Institute for Neurological Disorders and Stroke (NINDS) and the DoD’s Defense Advanced Research Projects Agency (DARPA) enabled the Pitt team to pair a brain-computer interface with a dexterous robotic arm. Dr. Schwartz had taught monkeys to feed themselves using their thoughts to control first a simple arm and gripper, and later a human-like arm developed at the Johns Hopkins University Applied Physics Laboratory. The next step was to test the technology in people who were paralyzed.
The First Human Trial
Based on the CTSI-funded mapping work, Wang received a critical KL2 Mentored Research Investigator Training Award in 2010. Naming Boninger and Schwartz as his senior mentors, the grant enabled Wang to take the lead on a new clinical trial combining the mapping data from his pilot work with the ECoG technology, already in clinical use with epilepsy patients, and put the device into a paralyzed patient.
"The KL2 award really provides the structure to develop this kind of work," Wang said. "I could bring my questions to team members from varied backgrounds and disciplines.”
Work with the first patient began in August of 2011. The patient learned to manipulate objects with the robotic arm using only his thoughts. The soon-to-be-published data from this experiment actually showed changes in brain patterns over time as the patient became better at the tasks. The patient's brain appeared to be learning — and so was the research team.
Experience Pays Off
Schwartz and Boninger now lead a year-long experiment with their second human patient using a different technology from the earlier ECoG device. This smaller, more sensitive electrode grid from Blackrock Microsystems penetrates into the brain rather than sitting on its surface. Before the experiment could begin, the Pitt IRB and the FDA had to give permission to test the device in humans. DARPA brought the FDA into discussions immediately, fast-tracking this permission step. With help from regulatory experts at the Pitt CTSI and championed by Dr. Jennifer Collinger, another bioengineer and faculty in Boninger's department, the study team wrote the FDA application and created a protocol to pursue the research in paralyzed humans. Both were approved in only nine months; typically this is a process that can take years.
Armed with the surgical input from the previous study and the monkey data using the robotic arm, their protocol and the FDA application were solid. "Nothing about it surprised the FDA because we had been having discussions with them all along," said Boninger. Because of the technology’s potential to help amputee soldiers, the group was able to garner funding from both DARPA and the VA. "Once you have this multidisciplinary collaboration in place," Wang explained, "the diversity of skills allows your research team to reach out to different agencies for funding."
With the new setup installed in her brain, the study volunteer moved the robotic arm with only her thoughts less than one week after surgery. After 13 weeks of controlling the arm with her thoughts, the process was routine. Her goal was to take a bite of chocolate. The fact that she could and did was a huge accomplishment not only for her but also for the study team.
Looking Ahead: Applying the Technology
The team continues to develop both technologies in parallel. "We want to be able to make this work for the long term," said Boninger, "but we have lots of science to do first. That is why we think it is critical to continue to investigate both technologies."
"We already have seen how well this works in a patient with a neurodegenerative disease," said Tyler-Kabara. "That opens the door for applications that may help those with spinal injuries, amputees and those with cerebral palsy. The population that could benefit from this technology is limited only by our imagination."
Schwartz is quick to insist that this is still a research tool. "It is not robust enough to be used widely, but we could have patients using it at home in a year or two in a research protocol," he said. The goal is a fully implanted device that gives patients feeling and control that others can’t see.
To make this a real treatment alternative for patients, the team continues to rely on CTSI resources. They are using the Pitt CTSI Research Participant Registry to help them find study volunteers. This independent registry has more than 38,000 individuals who have indicated a willingness to consider participation in clinical trials.
The next big steps in making this available for patients will be getting FDA approval and then commercialization. "This will involve new initiatives, and we will need help," said Boninger. "We know we can rely on CTSI expertise to get us there."
Posted January 2013