A team of scientists and physicians at the University of Pennsylvania will lead a four-year effort worth as much as $22.5 million to develop next-generation technologies to restore memory function in people who suffer from memory loss due to disease or traumatic injury. The project, which is in support of President Obama’s BRAIN Initiative, will combine research on the basic mechanisms of memory function with the development of systems designed to electrically stimulate discrete regions of the brain.

“This type of interdisciplinary research for the public good epitomizes Penn’s core values,” said Steven Fluharty, dean of the University of Pennsylvania’s School of Arts & Sciences. “We are excited to bring together some of the world’s top scientists, clinicians and engineers, here at Penn and beyond, to do the foundational work that could one day lead to a cure for memory loss.”

The Penn effort is led by Michael Jacob Kahana, professor of psychology and director of the Computational Memory Lab, and is part of the “Restoring Active Memory” program sponsored by the Defense Advanced Research Projects Agency. The Penn team also includes researchers from the Perelman School of Medicine and the School of Engineering and Applied Science.

Because memory is the result of complex interactions between widespread brain regions, the researchers will study neurosurgical patients who have had electrodes implanted in various areas of their brains for the treatment of neurological disease. By recording neural activity from these electrodes as patients play memory games, the researchers will measure “biomarkers” of successful memory function, patterns of activity that accompany the successful formation of new memories and the successful retrieval of old ones.

“Biomarkers of good memory function will guide our ability to stimulate the brain to synthesize patterns of neural activity conducive to proper memory function,” Kahana said. “To accomplish this we must first map the neural mechanisms of human memory in both time and space. By deciphering the unique spatiotemporal maps of good memory function in each participant, we can determine how to use brain stimulation to gently coax brain activity out of dysfunctional states and towards optimal ones.”

Solving this problem will involve recruiting neurosurgical patients with epilepsy and Parkinson’s disease, who ordinarily receive brain stimulation as part of their clinical treatment. These patients may elect to participate in the project’s research studies, which entail receiving safe levels of brain stimulation as they play memory games to determine if their memory can be improved by these interventions.

“If memory can be improved in patients who have electrodes implanted to treat epilepsy and Parkinson’s disease, and who frequently have mild memory impairment, then we will have gained extremely valuable information on how to restore normal memory function in patients with traumatic brain injury or Alzheimer’s disease,” Kahana said.

Patients will be recruited at the Hospital of the University of Pennsylvania along with six other major medical centers: Thomas Jefferson University Hospital, Dartmouth-Hitchcock Medical Center, Emory University Hospital, the University of Washington Medical Center, the Mayo Clinic and the National Institutes of Health Clinical Center. Neuroscientists, engineers and applied mathematicians from Boston University, Drexel University and the University of Washington will help to develop computational models of memory and algorithms to guide brain stimulation.

Other members of the Penn team include Gordon Baltuch, professor of neurosurgery; Kathryn Davis, assistant professor of neurology; Timothy Lucas, assistant professor of neurosurgery; and Joel Stein, assistant professor of radiology, all of Penn Medicine.

The portion of the project that will involve epilepsy patients will be led by Michael Sperling, the Baldwin Keyes Professor of Neurology at Thomas Jefferson University. 

“Epilepsy is often accompanied by severe memory loss, so these patients are graciously giving us a unique opportunity to better understand the fundamentals of memory,” Sperling said. “This project will be the first step on a long road to finding memory-improving treatments that could be an alternative or complement to the pharmaceutical approaches we currently have.”  

Gordon Baltuch, the director of Penn’s Center for Functional and Restorative Neurosurgery, is leading the arm of the project that will involve Parkinson’s patients.

“This multidisciplinary, collaborative effort to develop a neuroprosthetic device will go beyond treating Parkinson’s disease,” Baltuch said. “We’re taking the lessons we’ve learned in the clinical application of deep-brain stimulation and expanding the scope and power to treat a variety of memory disorders.” 

Beyond the advances in basic and clinical research, a major component of this effort is the development of next-generation technologies to enable real-time recording and stimulation of sites throughout the brain. This effort will be carried out through separate collaborations with Medtronic Inc. and with Neuropace Inc. Medtronic, whose FDA-approved deep brain stimulation systems have been implanted in more than 110,000 patients worldwide, will assist in the development of an investigational neural stimulation and monitoring system, which may lead to better understandings of the brain and how deep brain stimulation therapy can potentially restore normal brain function following injury or the onset of neuropsychological illness. Neuropace, whose RNS® System was FDA-approved in November to reduce the frequency of seizures in epilepsy patients who have not responded well to medications, will join the project to provide another platform for research in patients with implanted electrodes.

Under the terms of a cooperative agreement with DARPA, Penn will receive as much as $22.5 million for its work on the RAM program, with full funding contingent on meeting a series of technical milestones.

By the end of the four-year project, Penn aims to develop a fully implantable neural monitoring and stimulation system that could be used in the treatment of memory loss.

Fully anonymized data obtained during the course of this project will be made freely available via a Web portal being developed by Zachary Ives, professor of computer and information science in Penn’s School of Engineering and Applied Science, and Brian Litt professor of neurology in Penn Medicine and of bioengineering in Penn Engineering, along with Gregory Worrell of the Mayo Clinic.

“We believe sharing our anonymized data will benefit future research,” Kahana said,  “but beyond that we hope that all research projects involving human brain data follow this model of openness.”