By Blake Cole, Penn Arts and Sciences
When Michael Kahana and his collaborators landed on the idea of using brain implants to track brain activity in patients who are awake and alert, it was akin to a research goldmine.
The research is integral to the Restoring Active Memory (RAM) project, a grant initiative funded by DARPA (Defense Advanced Research Projects Agency) awarded to Kahana in 2014. RAM is a centerpiece of Penn Arts and Sciences’ Harnessing the Power of the Brain initiative, which seeks to bring together researchers from myriad disciplines to decipher the complex relationship between brain activity and the vastness of human intelligence and behavior. The long-term goals of the RAM project are to deliver new treatments to those who have experienced a traumatic brain injury, such as veterans returning from combat. The hope is that the research might also be used to help patients with a broad range of ailments, like Alzheimer’s disease.
The research team makes up one of half a dozen or so labs around the world that are pursuing direct human brain recording in order to understand memory. “Early in my career I had the incredible fortune of meeting a talented young neurosurgeon, Dr. Joseph Madsen of Children’s Hospital, Boston. Joe invited me to visit the epilepsy monitoring unit where I met patients whose seizures were being monitored and evaluated with surgically implanted electrodes,” says Kahana, a professor of psychology and director of the Computational Memory Lab. “I remember quite vividly watching one of the teenagers play a Nintendo video game while we observed the patient’s brain activity recorded from more than 100 electrodes on a monitor in an adjoining room. I said, ‘This is incredible, who is analyzing these data?’ I then learned that the data were routinely deleted at the end of [each session] due to the very limited storage capacity of computers in the 1990s.”
After this serendipitous encounter, Kahana began an intensive 20-year program of research to use invasive neural recordings to study the brain’s signals underlying human memory function. These studies revealed the critical importance of neural oscillations both for human spatial and verbal memory. During the subsequent 20 years, Kahana and has students have intensively studied the neural basis of human memory in neurosurgical patients. Direct electrical recordings from the human brain not only expose which regions give rise to memory-related signals—they also reveal the precise timing and character of those signals, revealing a symphony of brain activity that takes place whenever you store or retrieve information.
In fall 2013, Kahana learned about the ambitious DARPA program and assembled a team, led by Penn but including eight other leading medical research centers, and commercial-partner Medtronic, to study novel approaches to using brain stimulation to boost memory. Kahana’s team had already identified reliable methods for decoding when memory would be likely to succeed or fail.
Kahana surmised that if he could decode these signals rapidly, they could be used to determine when, where, and how to stimulate the brain to boost memory. The key idea, according to Kahana, is that “memory is highly variable from moment to moment and day to day. By knowing whether the memory system is functioning well or poorly, we can precisely tune the parameters of brain stimulation to be helpful rather than harmful.” To accomplish the “when,” it is critical that to stimulate the brain during periods when it is not working at its optimal level, such as a failure of memory. “You don’t want to disturb the brain when it’s working well,” says Kahana, who was this year’s recipient of the Warren Medal, the highest honor for experimental psychology. “You want to coax it out of the bad state and into a good state.”
To determine exactly when to stimulate the brain, Kahana’s team developed closed-loop systems that could deliver precisely timed stimulation to specific brain structures just as memory was predicted to fail. “When we applied stimulation in this manner, we were able to reliably boost recall performance by more than 15 percent,” Kahana says. This degree of change is equivalent to the decline in memory observed over two years of progression of Alzheimer’s disease, suggesting that closed-loop stimulation approaches may one day be used to treat this condition. These findings, recently published in Nature Communications, have been widely covered in publications such as The New York Times and National Public Radio.
“We have a lot more testing to do, but we believe that closed-loop stimulation approaches could be effectively used to treat memory loss in a variety of neurological conditions” Kahana says.
When it comes to working with the study participants, Kahana says the patients he and his collaborators oversee are a very special group. “This is an incredibly giving, empathetic set of people who want to do everything that they can to reduce the suffering of others. They participate in these experiments and teach us how the brain works, and their contribution is invaluable.”
Blake Cole is associate director of communications in Penn Arts and Sciences.
The green fluorescent ‘dots’ above show where Exendin-4, an FDA-approved drug used to treat diabetes and obesity, ends up in the brain. The drug activates receptors for glucagon-like peptide 1 or GLP-1, a hormone that reduces food intake. The blue and red coloring indicate neurons and astrocytes, respectively.
By Michele Berger
Cocaine and other drugs of abuse hijack the natural reward circuits in the brain. In part, that’s why it’s so hard to quit using these substances. Moreover, relapse rates hover between 40 and 60 percent, similar to rates for other chronic conditions like hypertension and Type 1 diabetes.
Penn behavioral pharmacologist and neuroscientist Heath Schmidt studies how long-term exposure to drugs such as cocaine, nicotine, and prescription opioids affects the brain and how these changes promote relapse in someone who has kicked the habit. Two recent papers, published in Addiction Biology and Neuropsychopharmacology, investigated a novel treatment for cocaine addiction, something that touches 900,000 people in the United States annually.
“As a basic scientist I’m interested in how the brain functions during periods of abstinence from cocaine and other drugs and how neuro-adaptations in the brain promote relapse back to chronic drug taking,” he explains. “From the clinicians’ perspective, they’re looking for medications to try to prevent relapse. Our goal as basic scientists is to use animal models of relapse to identify novel medications to treat cocaine addiction.”
Schmidt and colleagues from Penn Nursing and Penn Medicine had hypothesized that the neural mechanisms and neural circuits in the brain that play a role in food-seeking might overlap with those key to drug-taking. Through several experiments, they discovered that drugs that activate receptors for glucagon-like peptide 1 (GLP-1), a hormone that reduces food intake and blood glucose levels, could actually decrease the desire to seek out cocaine. What’s more, there are several FDA-approved medications used to treat diabetes and obesity that already target GLP-1 receptors.
“One of the first questions we had—and we were really just kind of curious—was, does cocaine at all affect circulating levels of metabolic factors like leptin, insulin, GLP-1 that have been shown to regulate food intake?” says Schmidt, whose primary appointment is in Penn’s School of Nursing.
The research team got its answer from a simple experiment with a rat animal model: Blood drawn after 21 days of cocaine intake revealed decreased levels of the GLP-1 hormone. Though the primary cells that synthesize and release this hormone are found in the small intestine, there’s also a source in the brain called the nucleus tractus solitarius.
“Knowing all of this got us interested in GLP-1,” Schmidt says. “Does it actually play a role in modulating cocaine-mediated behaviors?”
From there, the research team homed in on GLP-1 receptors and the drugs that activate them, what are known as receptor agonists. To test the efficacy of the medications in question, Schmidt and colleagues used an animal model of relapse with rats. For a three-week period, the rats could press a lever for intravenous infusions of cocaine as frequently as they desired. On average, the animals self-administered 28 infusions of cocaine each day.
The scientists then swapped out the cocaine for saline, leading to a period of withdrawal. Lever-pressing rates dropped significantly.
“At that point, we considered drug-taking to be extinguished,” Schmidt says. “We then reinstated drug-seeking by re-exposing the rats to the drug itself or to cues paired with the drug during the self-administration phase, like a light that comes on when the lever gets pressed.”
Once again rats depressed the lever at high rates, an indication that they were seeking the drug—akin to relapse in a human who is addicted.
The researchers next pretreated the animals with one of the FDA-approved drugs intended for diabetes and obesity treatment, Exendin-4, to determine whether it might reduce or altogether block cocaine-seeking. Results showed a significant decrease in drug-craving and -seeking, both after an acute injection of cocaine and from re-exposure to environmental cues during withdrawal.
“This tells us Exendin-4 can block the effects of cocaine itself but also condition stimuli previously paired with cocaine,” Schmidt notes. “This was really exciting because it’s the first demonstration that the GLP-1 system, and the drugs that target this system, could potentially play an important role in cocaine seeking and relapse. The other really interesting aspect of these studies are the doses.”
GLP-1 receptor agonists are known to cause nausea and vomiting at pretty high rates in diabetic and obese patients who use them, so Schmidt and colleagues wanted to ensure that the reason for a decrease in cocaine-seeking wasn’t from animals being sick. They identified doses that both reduced cocaine-seeking and did not produce adverse effects. A follow-up experiment that infused the GLP-1 agonist directly into the brain replicated the findings. Taken together, these findings indicate that low doses of a GLP-1 receptor agonist can selectively reduce cocaine-seeking without causing nausea.
As a final step, the researchers isolated the brain pathway able to boost GLP-1 signaling, by using a fluorescent dye to track where the drugs actually went in the body after they were administered.
“With these two papers, we’ve shown for the first time that central GLP-1 signaling plays an important role in cocaine-seeking,” Schmidt explains. “We’ve identified systematic and intra-cranial doses of GLP-1 receptor agonists that reduce cocaine-seeking and don’t produce adverse effects, and we think that if you increase GLP-1 signaling in the brain in general, you can reduce cocaine-seeking in rats and, potentially, craving-induced relapse in humans.” To begin testing this, Schmidt’s team is collaborating with researchers at Yale University to screen the efficacy of these drugs in a population of humans addicted to cocaine.
Beyond that, Schmidt says he’s hopeful these results have potential for drugs of abuse beyond cocaine, too. However, he adds, much more research is needed before this can be stated conclusively. “There is a lot we don’t know about the GLP-1 system in the brain,” he says. “What is the exact circuitry in the brain? Is this signaling the same as what mediates food intake or is it slightly different? Does cocaine change it in any way? We’re working on that.”
Funding for the research published in Neuropsychopharmacology was supported by National Institutes of Health grants R01 DA037897, T32 DA028874, F32 DK097954, K01 DK103804, and R01 DK096139, as well as a Vagelos Undergraduate Research Grant from the Center for Undergraduate Research & Fellowships at the University of Pennsylvania.
Funding for the research published in Addiction Biology was supported by National Institutes of Health/National Institute on Drug Abuse grants R01 DA037897, K01 DA031747, and R01 DA041513.
Heath Schmidt is an associate professor of nursing in the School of Nursing and an assistant professor of psychiatry at the Perelman School of Medicine. He is also part of the Center for Neurobiology and Behavior.
Other contributors to the research included Nicole Hernandez, Kelsey Ige, Elizabeth Mietlicki-Baase, Gian Carlo Molina-Castro, Christopher Turner, and Matthew Hayes of Penn Medicine; and Bernadette O’Donovan and Pavel Ortinski of the University of South Carolina School of Medicine.
Michele Berger is a Science News Officer in University Communications.
The coal industry is changing, with machines doing work once done by miners and different energy sources gaining ground. But this shift is about more than economics; it’s about people, too. A forthcoming report from the Kleinman Center offers a range of strategies to help revitalize Pennsylvania’s coal communities in the medium- to long-term.
By Christina Simeone, Kleinman Center for Energy Policy
From Penn’s campus in bustling Philadelphia, it may be hard to comprehend that Pennsylvania is embroiled in a crisis concerning coal miners and coal-dependent communities.
The mental-health situation in Appalachia looked troubling a decade ago. A 2008 report from the University of Chicago, commissioned by the Appalachian Regional Commission, found a higher prevalence of mental-health disorders—such as serious psychological distress and major depressive disorder—in Appalachia compared to the rest of the nation. These mental-health diagnoses were independent from substance abuse and particularly acute in economically distressed areas.
A decade later, the situation does not seem to have improved. In 2017, the University of Chicago released a follow-up report commissioned by the Appalachian Region Commission examining trends with three “diseases of despair” in Appalachia: substance abuse (alcohol, prescription drugs, and illegal drugs), suicide, and liver cirrhosis (alcoholic liver disease). The study found the combined mortality rate from diseases of despair was 37 percent higher in the Appalachian U.S. compared to non-Appalachian U.S. Most notably, the 25- to 44-year-old age group in the Appalachian U.S. had a 70 percent higher mortality rate from diseases of despair compared to non-Appalachian U.S. The report notes this has significant implications for economic development, as individuals in their prime working years are most heavily impacted by these diseases.
It may or may not be coincidence that Pennsylvania’s opioid epidemic is affecting a similar demographic. According to a 2016 report from the U.S. Drug Enforcement Agency and the University of Pittsburgh, Pennsylvania saw a 37 percent increase in drug overdoses from 2015 to 2016. In 2016, approximately 13 people per day died of drug overdoses, the majority of which were opioid related (85 percent), white (77 percent), male (70 percent), with the most-impacted age group being 25 to 34 years old. On top of this, on a population-adjusted basis, many rural counties home to distressed coal communities had some of the highest drug-related death rates in the state.
These health-related outcomes are troubling, and while not claiming causality, these outcomes are perhaps intuitively not surprising after considering the recent history and lack of opportunities available in many of these rural coal towns and communities.
Pennsylvania’s coal mining history began in the 1700s, with Appalachian coal being used to warm homes, fuel power plants, and make the steel that built the industrial revolution. Bustling towns grew around coal mines across rural Pennsylvania to house, feed, and entertain miners and their families. But today, many of these same coal communities are in economic distress, with profoundly negative psychological and health outcomes for the most impacted individuals.
The Kleinman Center for Energy Policy performed research for the Pennsylvania Small Business Development Center’s federal grant exploring strategies to assist individuals and businesses impacted by changes in the state’s coal economy.
Although the research focused on energy market dynamics, demographic changes in the state, and economic development strategies, the most gripping insights came from stakeholders within Pennsylvania’s coal communities who conveyed the human experience of the coal downturn.
To understand the human experience, one has to first understand the downturn itself. In the early days of coal mining, the industry relied on human laborers. But for decades now, machines have more quickly and efficiently been doing the work of miners, resulting in coal production increasing and employment decreasing. This long-term trend of declining coal mining employment contributed to economic stress in coal mining towns.
Other factors served to compound this stress, such as reduced demand for coal from the domestic steel industry, increased regulation of coal as scientists learned more about the health and environmental impacts of coal extraction and combustion, and increased competition from lower-priced coal extracted from other areas of the nation.
However, the rapid rise of cheap and abundant natural gas—extracted by machines from Pennsylvania’s Marcellus Shale deposits—has dealt a swift and devastating blow. Within just a decade (between 2005 and 2014), coal-fired power plants ceded almost 20 percent market share in the regional power market to gas-fired generation, and coal mining in Appalachia declined by 45 percent, more than twice the national decrease of 21 percent.
Distressed coal communities in Pennsylvania generally share many common demographic characteristics, including high unemployment, aging populations, deteriorating or insufficient infrastructure, and educational attainment levels that are lower than state and national averages. As people born, raised, and educated in these communities move out, new, educated populations generally do not move in, leading to a “brain drain” of educated workers. These and other factors make it difficult to attract new business into these communities.
There are efforts underway to assist distressed coal communities and individuals, but it’s too soon to determine their efficacy. And numerous barriers exist. Many individuals can’t afford to relocate, because plummeting property values—stemming from community distress (i.e., high unemployment, eroding tax base, and deteriorating infrastructure)—have caused them to be underwater on their mortgages. Some workers can’t take advantage of retraining opportunities because they can’t financially support their families during the education period. And, some employers say there are jobs, but they can’t find qualified people who can pass a drug test.
And although coal mining exposes workers to inhospitable working conditions, negative respiratory health effects, and even risk of fatality, mining jobs may be some of the best around (when available), paying a $30,000 wage premium to the average Pennsylvania industrial wage. Plus, there is a rich and important cultural and generational connection to coal in these areas, making it difficult for many to imagine the potential for a drastically different future.
The Kleinman Center’s forthcoming report, to be published later this month, focuses on a range of strategies to help revitalize Pennsylvania’s coal communities in the medium- to long-term. There is much work still to be done, to address the immediate needs of these people and places, and to ultimately stem the crisis occurring within our Commonwealth. (Click here to read an executive summary of the Kleinman Center’s findings.)
Christina Simeone is the director of policy and external affairs for The Kleinman Center for Energy Policy.
Research from doctoral candidates at the Annenberg School for Communication measured brain activity in real time as study participants viewed the headlines and abstracts of 80 health articles from The New York Times. Participants then rated how likely they were to share those articles.
By Julie Sloane, Annenberg School for Communication
It is a question that has mystified countless people: Why does one article spread like wildfire through social media and another—seemingly similar—doesn’t? How does your brain decide what is valuable enough to read and share?
In research published in 2017 in the Proceedings of the National Academy of Sciences and Psychological Science, Christin Scholz and Elisa Baek, students in the doctoral program at Penn’s Annenberg School for Communication, documented for the first time the specific brain activity that leads us to read or share articles—in this case, health articles from The New York Times. And by looking at this specific pattern of brain activity in 80 people, they also could predict the virality of these articles among real New York Times readers around the world.
Fundamentally, explains researcher Emily Falk, director of Penn’s Communication Neuroscience Lab, specific regions of the brain determine how valuable it would be to share information, and that value translates to its likelihood of going viral.
“People are interested in reading or sharing content that connects to their own experiences, or to their sense of who they are or who they want to be,” she says. “They share things that might improve their relationships, make them look smart or empathic, or cast them in a positive light.”
By using fMRI, Scholz and Baek were able to measure participant brain activity in real time as readers viewed the headlines and abstracts of 80 New York Times health articles and rated how likely they were to read and share them. Articles were chosen for their similarity of subject matter—nutrition, fitness, healthy living—and number of words.
The researchers honed in on regions of the brain associated with self-related thinking, regions associated with mentalizing—imagining what others might think—and with overall value.
Although it may seem intuitive to expect that people would think about themselves in deciding what to read and about others in deciding what to share, the researchers found something else: Whether choosing to read for themselves or what to recommend to others, people actually think about both, the neural data suggest.
In fact, the researchers reported in Psychological Science that thinking about what to share brought out the highest levels of activity in both of these neural systems. “When you’re thinking about what to read yourself and about what to share, both are inherently social, and when you’re thinking socially, you’re often thinking about yourself and your relationships to others,” Baek says. “Your self-concept and understanding of the social world are intertwined.”
A second study, published in PNAS, shows how these brain signals can be used to predict virality of the same news articles around the world.
When stories go viral through the 4 billion Facebook messages, 500 million tweets, and 200 billion emails shared daily, they can have a real effect on our health, politics, and society. But not all articles are shared equally. Why do some articles get shared while others don’t?
By looking at brain activity as 80 test subjects considered sharing the same New York Times health articles, researchers predicted an article’s virality among the actual New York Times readership, which shared this group of articles a combined 117,611 times. They found that activity in the self-related and mentalizing regions of the brain combine unconsciously in our minds to produce an overall signal about an article’s value. That value signal then predicts our desire to share.
Though the pool of test subjects—18-to-24-year olds, many of them university students, living around Philadelphia—represented different demographics than the overall New York Times readership, brain activity in key brain regions that track value accurately scaled with the global popularity of the articles.
“If we can use a small number of brains to predict what large numbers of people who read The New York Times are doing, it means that similar things are happening across people,” Scholz says. “The fact that the articles strike the same chord in different brains suggests that similar motivations and similar norms may be driving these behaviors. Similar things have value in our broader society.”
Scholz acknowledges that exactly how we’re thinking about ourselves and others varies from person to person. For example, one person might think that an article will make their friends laugh, while another might think that sharing it will help their friend solve a particular problem. But neural activity in regions associated with the self and with social considerations serves as a type of common denominator for various types of social and self-related thinking.
“In practice, if you craft a message in a way that makes the reader understand how it’s going to make them look positive, or how it could enhance a relationship,” Scholz says, “then we predict it would increase the likelihood of sharing that message.”
Julie is director of communications for the Annenberg School for Communication.
Image: Neurons (green) were exposed to two antiretroviral drugs, lopinavir (LPV), darunavir (DRV), vehicle (VEH) or left untreated. Exposure to lopinavir induced loss of neurons by 24 hours, while exposure to darunavir did not. Cellular nuclei are shown in blue.
By Katherine Unger Baillie, University Communications
When it comes to treating HIV/AIDS, antiretroviral drugs such as protease inhibitors can be a double-edged sword.
“Protease inhibitors are very effective antiviral therapies, but they do have inherent toxicities,” says Kelly Jordan-Sciutto, chair and professor in Penn Dental Medicine’s Department of Pathology.
These drugs, while credited with cutting in half deaths from HIV/AIDS, have been implicated in contributing to HIV-associated neurocognitive disorders (HAND). Forgetfulness, confusion, and behavior and motor changes are among the symptoms.
In recent research, including a publication in the American Journal of Pathology, Jordan-Sciutto and colleagues have found key pathways through which the therapies seem to harm the brain—pathways that could eventually be targeted by drugs to counter some of the cognitive impairments experienced by patients undergoing treatment.
Earlier studies by the Penn team generated evidence that HIV patients taking protease inhibitors had overactive stress-response pathways, including one known as the unfolded-protein response. They also knew that the unfolded-protein response could activate the enzyme BACE1. This latter finding intrigued the researchers, for BACE1 snips amyloid precursor protein to produce beta amyloid—the same molecule that clogs up the brains of Alzheimer’s patients. Perhaps, they thought, the unfolded-protein response could be generating damaging BACE1 activity in HIV patients as well.
The research team confirmed that the protease inhibitors ritonavir and saquinavir—both still widely used, especially in Africa—indeed triggered an increase in both amyloid precursor protein and in BACE1. Then, when they administered the drugs to cells in culture, they discovered increases in signs of the unfolded protein response, as well as jumps in BACE1 expression and amyloid precursor protein processing, representing neuronal damage. A BACE1 inhibitor applied to the cells prevented the drug-induced damage.
More recent work published in the Journal of Neuroimmune Pharmacology, led by Caglay Akay-Espinoza, a research assistant professor who works with Jordan-Sciutto, confirmed that certain newer generations of HIV drugs, both protease inhibitors and another class called integrase strand transfer inhibitors, can also lead to neuron damage. Jordan-Sciutto, who is also director of biomedical graduate studies at Penn, says the findings are not a reason to abandon effective HIV/AIDS therapies but do suggest that a drug that blocks BACE1 activity might put a dent in neuron damage.
“Our findings may cause us to rethink how we’re using these drugs,” she says, “and even consider developing targeted adjunctive therapies to reduce some of these negative effects.”
Katherine Unger Baillie is a Science News Officer in University Communications.