ARTICLE IN BRIEF
The Defense Advanced Research Projects Agency is funding major research initiatives to develop the next generation of implantable neuroprosthetics for use in patients with memory problems and other cognitive deficits.
The Defense Advanced Research Projects Agency (DARPA) has awarded nearly $40 million to two independent teams of neurologists, neurosurgeons, and neuroscientists at the University of California, Los Angeles (UCLA) and the University of Pennsylvania (UPenn) to develop the next generation of implantable neuroprosthetics for use in patients with memory problems and other cognitive deficits.
UCLA scientists are working with DARPA-funded bioengineers from Lawrence Livermore National Laboratory to develop smaller and more powerful thin-film interfaces that can fit hundreds of electrodes onto a single lead.
DARPA's interest stems from the fact that 270,000 military personnel have been diagnosed with traumatic brain injury since the year 2000. Many of these patients have a long list of cognitive and behavioral problems as a result of their injuries, and the most pressing of these are memory issues. The federal agency believes that advances in deep brain stimulation (DBS) to enhance memory in patients with mild Alzheimer's disease, as well as successes in using electrode stimulation to treat severe depression, suggest that the technology could be developed even further. Ultimately, DARPA hopes that the devices could be used to help military personnel.
“We see this as a transformative approach to interact with the brain,” said Justin Sanchez, PhD, program manager for DARPA's Restoring Active Memory (RAM) and Systems-Based Neurotechnology for Emerging Therapies (SUBNET) programs. RAM focuses on restoring memory and SUBNET is designed to study the effectiveness of these devices in treating a range of psychiatric disorders, including post-traumatic stress disorder and depression.
“We're talking about a whole systems approach to the brain, not a disease-by-disease examination of a single process or a subset of processes,” said Dr. Sanchez. “We hope to be able to sense, process, and stimulate neural circuits in a very direct way.”
Should the studies be successful, Dr. Sanchez and others involved in these projects believe they could revolutionize treatment for all types of brain problems. Current DBS surgeries implant electrodes in specific areas of the brain, depending on the condition, and the stimulation settings are set based on the alleviation of specific symptoms. Several companies have designed devices for epilepsy patients that can “sense” abnormal signals and stimulate the appropriate brain region to prevent a seizure.
DARPA hopes to use this technology to identify networks involved in different types of memory and cognitive processes and see whether it is possible to stimulate specific groups of neurons to restore memory. These devices are able to record the inner workings of the brain with high spatial and temporal resolution and can “sense” when and where there are problems with neural connections. Then, scientists will attempt to figure out how the brain decodes neural signals during any number of cognitive events, such as acquisition or recall, and test whether stimulation can fix neural signals involved in memory that are damaged by disease or injury.
First, the researchers must build the devices and test them in civilian patients who are undergoing neurosurgery for other reasons, Dr. Sanchez explained. They will ask these patients to allow them to implant electrodes to record and stimulate specific sites that regulate memory, and give them word recall tests to see whether their memory improves. If it works, they will move on to testing in patients with traumatic brain injury.
“Despite increasing aggressive prevention efforts, traumatic brain injury remains a serious problem in military and civilian sectors,” said Dr. Sanchez. “Through the RAM program, DARPA aims to better understand the underlying neurological basis of memory loss and speed the development of innovative therapies.”
Dr. Sanchez acknowledged, however, that it could be many years before military personnel would benefit from the technology.
WORK AT UCLA
In a 2012 paper published in the New England Journal of Medicine, Itzhak Fried, MD, PhD, professor and director of the Epilepsy Surgery program at UCLA, reported on seven patients undergoing a workup for epilepsy surgery who had agreed to be part of a study on DBS and memory. The research team had implanted electrodes in these patients to detect and record seizure activity.
The patients were asked to play a computer game in which they had to shuttle people around a city; Dr. Fried and his colleagues found that the patients were able to navigate faster and more efficiently when the electrodes stimulated the entorhinal cortex. Electroencephalogram recordings showed that DBS triggered a resetting of the phase of a theta rhythm in the hippocampus, which is thought to be critical to the formation of memories.
With DARPA funding, Dr. Fried and his colleagues at UCLA will continue to collect neural information from these patients. They want to understand how the brain codes these so-called “declarative memories,” the recall of facts and events. They will also test new models to determine how stimulation might be able to help the brain re-establish lost memories, and how patients form new memories after a head injury.
For the first year of the study, Dr. Fried and his colleagues will use information gleaned from his DBS studies in epilepsy patients to build computational models of the entorhinal cortex and hippocampus networks. UCLA is working with scientists at Lawrence Livermore to build a device that is 10 times smaller in size and far more powerful than existing devices. Once the technology is tested in the lab, they will head into clinical trials in patients with traumatic brain injury. The electrodes will be placed in the entorhinal cortex and hippocampus of these patients.
Dr. Fried is working with Satinderpall Pannu, PhD, director of the Lawrence Livermore Center for Micro- and Nanotechnology and Center for Bioengineering, who has been building the next generation of biocompatible neural interfaces.
“The goal is to build a prototype device that can ultimately be used for clinical trials in patients with traumatic brain injury,” said Dr. Pannu.
Lawrence Livermore scientists are also working on the SUBNET project.
STUDIES UNDERWAY AT UPENN
Michael Jacob Kahana, PhD, director of the Computational Memory Laboratory at UPenn, is overseeing the DARPA studies at the university. He sees memory as a complex network that fans out to many brain regions. He, too, wants to restore memories by stimulating neural tissue; he is also set to study epilepsy patients who will undergo neurosurgery to control their seizures and Parkinson's disease patients who will be getting deep brain stimulators implanted.
Once they have mapped out these patterns of neural activity, the researchers hope they will be able to simulate the same activity in a brain with poor memory. A multi-disciplinary team from UPenn is collaborating with scientists and bio-engineers at Thomas Jefferson University Hospital, Drexel University, Dartmouth-Hitchcock Medical Center, Emory University Hospital, the University of Washington Medical Center, Boston University, the Mayo Clinic, and the National Institutes of Health Clinical Center.
The UPenn team is also designing an implantable neural monitoring and stimulating system.
Neuroscientists and neuroethicists who spoke with Neurology Today said they were excited by the possibility that these devices may be able to respond to a person's environment and record the events across an integrated closed-loop circuit.
“The technology is cutting edge,” said James Giordano, PhD, a professor of integrative physiology and chief of the neuroethics studies program in the Center for Clinical Bioethics at Georgetown University Medical Center. Dr. Giordano was appointed to DARPA's Neuroethics, Legal and Social Issues Advisory Panel.
“It is not just dropping in an electrode, but they can record locally and at a more systemic level,” he said. “Ethically, it provides a range of options in intervening in a number of brain problems. It is also a useful learning tool.”
“The beauty of this system and the nature of the technology and the sophistication of the science is that there is great flexibility,” he added.
But there are ethical dilemmas that must be addressed before these devices can make their way into the clinic, he warned. There is a growing concern that the manipulation of brain networks could be used as a form of mind control. Last year, scientists at the Massachusetts Institute of Technology were able to stimulate the hippocampus of a mouse and trick it into thinking it was receiving foot shocks when there were none. That these devices will be tested for the treatment of neuropsychiatric conditions suggests to Dr. Giordano that “we need to develop a stance of preparedness to guide the ways that neuroscience can and will be used — and possibly misused,” he said.
Joel Voss, PhD, an assistant professor of medical social sciences and neurology at the Northwestern University Feinberg School of Medicine, wondered whether patients would accept the risk of brain surgery to restore their memory. “I liken it to the Manhattan Project,” he said. “It may not work, but what it tells us about the brain can be very useful.
“What's more, identifying signals of abnormal memory processing and injecting a new signal may not even work to correct the memory problem,” he added. “Treating epilepsy is an easy problem compared to what these scientists are now trying to do to treat traumatic brain injury and neuropsychiatric diseases. This is an uncharted territory.”
In August, Dr. Voss and his colleagues published a study in Science where they used magnets on the surface of the skull to stimulate a cortical structure in and around the hippocampus. They conducted the study in healthy volunteers and found that transcranial magnetic stimulation improved memory scores by 20 to 25 percent compared to volunteers who did not undergo stimulation. Subsequent brain scans showed increases in communication between networks that link the hippocampus to the parietal cortex in those who received stimulation. However, it is not known how long the improvement in memory will last.
EXPERTS COMMENT: IMPLANTS TO IMPROVE MEMORY