Study participants repeatedly press a lever on a large machine to make nickels slide out of a tube and drop into a cup. The coins pile up, but this activity in the Food and Drug Administration’s National Center for Toxicological Research (NCTR) laboratory at nearby Arkansas Children’s Hospital (ACH) isn’t a game of luck. It is a game that helps researchers compare important brain functions in children and animals—specifically their memory, attention, motivation, and time perception. The results provide the agency with important insights for the evaluation of the effects of pediatric drugs on psychological processes.
NCTR investigators have been studying brain function using this approach since 1988. They recruit human participants from ACH in Little Rock. The animal counterparts—monkeys—that play nearly identical games as the children are housed, cared for and tested at NCTR some 35 miles away.
So why are they doing this research? It is standard practice for the safety and effectiveness of new drugs to be tested in animals before these drugs are studied in humans. Unfortunately, it is sometimes difficult to predict how a new drug might affect brain function in humans based on the data obtained in animals. That’s because the types of tests given to assess brain function in animals often are different from the types of tests given to humans. By having animals and humans take exactly the same tests, researchers hope to be able to better predict the effects of drugs in humans using data obtained from animals.
It is hoped that the findings from these studies will help FDA, health care providers and parents make better informed decisions about medications for children—and to know more about how these medications might affect children’s brain function.
How the Testing Works
“We recruit a lot of our children from the general pediatric clinic. It’s a very broad sample and very diverse in terms of ethnicity, race, gender and age,” says John Chelonis, Ph.D., an NCTR research psychologist. Like all research involving human subjects, this study is subject to the many regulations designed to protect people of all ages who participate in clinical studies. “With human research,” Chelonis adds, “there are a lot of safeguards. If children decide they don’t want to play at any time, they can stop.”
The investigators have tested about 3,000 children since the lab opened. They see an average of eight to nine children per week, and the kids are always accompanied by consenting guardians.
Other NCTR staff train monkeys to participate in the research. The animals work for banana-flavored food pellets. “But they have to practice until they finally understand the rules of the games,” says Merle Paule, Ph.D., director of the Division of Neurotoxicology at NCTR. Some primates have been playing these games for almost 10 years. Once they learn the rules, which often takes months of trial and error performance, they can perform some games with accuracies of 95 percent or more.
“One of the important things about these games or tests is that they’re nonverbal,” says Paule. He explains that young kids don’t have language skills yet, and monkeys have none, and it’s the nonverbal nature of these tests, as opposed to traditional psychological tests, that makes more direct comparisons between the two groups possible.
Researchers study children who have attention deficit hyperactivity disorder (ADHD) and depression, and those who do not. “We try not to interfere with these kids’ treatment,” says Chelonis. “For instance, a lot of kids might be on their ADHD medication only during school days, and they’re off it on the weekends. So when we wanted to test the children when they were off their medication, we would typically schedule their sessions for the weekends when they were off of their medication.”
Researchers assess whether children’s responses vary in the presence or absence of medication and analyze the results based on gender and age. One of the tests that involves repeatedly pushing a lever on the behavior panel measures motivation. Children sit in front of the panel, which is positioned against a wall. They’re told to press one of the levers to get nickels. The first press releases one nickel. Children must press the lever 11 times for the second nickel (10 more than for the first nickel), 21 times for the third nickel, 31 times for the fourth nickel and so on, until the 10-minute game ends. The number of nickels earned depends on the strength of their motivation—how many times they press the lever.
Another game tests timing ability. For this, kids must hold one of the response levers down for at least 10 seconds, but not more than 14 seconds, to receive a nickel. It sounds simple. “But it’s a hard game,” says Chelonis. “It’s the cadence with which you count that gets you the nickel.” For this test, animals and kids tend to hold the lever down just long enough to meet the 10-second requirement. The timing ability of children with ADHD improves while on their medication. When children with ADHD are off their ADHD medication, they make more responses that are either too short or too long in duration compared to when they are on their ADHD medication.
What Researchers Hope to Accomplish
These FDA investigators are seeking to further validate their NCTR Operant Test Battery (OTB), the instrument they use to assess complex brain function in both children and monkeys.
They want to show:
How OTB task performance relates to IQ and other clinical tests that measure mental function in humans;
How OTB task performance relates to behavioral conditions such as ADHD, anxiety, and depression;
Whether OTB task performance is affected by drugs used to treat behavioral conditions such as ADHD; and
How children’s OTB performance compares to that obtained using animal models.
NCTR researchers have published many of their findings in a variety of scientific journals, including Experimental and Clinical Psychopharmacology, Behavioral Processes and Neurotoxicology and Teratology.
The value of animal models to predict clinical outcomes is important to FDA, Paule says. As researchers gain a better understanding of how animal OTB performance compares to human OTB performance, they’ll be able to develop better ways of using animal models to understand human behavior and better predict drug effects on human brain function. This eventually could help parents and medical professionals make more informed decisions about medication use and to understand the positive and negative effects that drugs may have on behavior.
FDA researchers are also studying the potential toxicity of general anesthetics and sedatives in children. Animal models suggest that a single episode of general anesthesia during critical stages of brain growth can cause lifelong deficits in brain function. The scientific community currently does not have enough human data to know whether this is a problem in the clinic, but it is suspected that prolonged or repeated exposures in children also could have cognitive consequences.
“Biology is basically the same across different species,” adds Paule, reflecting on NCTR’s comparative research. “Animals can do many things that we can do if we give them the right opportunity, and they can also show us a lot about drug effects if we can figure out how to look.”
