When people or animals with narcolepsy get very excited—when they are laughing uproariously or extremely happy—they often have attacks of cataplexy: They collapse on the floor for a minute or so, awake but paralyzed. To study the details of such attacks, Emmanuel Mignot at the Stanford University School of Medicine attempted to trigger them in his lab. But it is far from easy to make humans laugh in a lab setting, he says. "Humans are so unpredictable! What makes one person laugh may not seem funny to another. And it's particularly difficult to make people laugh when they are not relaxed."

Mignot tried everything: cartoons, comic books, even comedians, without much success. Sometimes a joke with sexual connotations made some men laugh but not women; at other times, it was the reverse. It's all very culture-bound, he says. Once, when he had a patient's head in a magnetic resonance imaging scanner to look for changes in his brain waves, Mignot was desperate enough to try tickling him. "It didn't work," he reports. "He started to move about in the scanner when he was supposed to be still." The researcher ended up relying almost exclusively on patients' own reports of their cataplexy episodes.

Dogs are much easier to work with, he says. "Of course, you can't make them laugh, but there are several ways of making them so happy that they have an attack." All you need to do with narcoleptic puppies is play with them, Mignot explains, or put them next to their littermates. "They start chasing each other around and biting each other's ears in a friendly way, having such a good time that suddenly they all collapse together." As the dogs grow older, however, they become very focused on status. Instead of playing with other dogs, they try to dominate them. At that point, Mignot switches to food.

"I give them something really special—for example, canned wet food like chunky beef with a lot of meat. It looks pretty disgusting, but it works well," he says. "Furthermore, it's easy to standardize. We can put 12 pieces of this meat on the floor and record how long it takes for an animal to eat them all. One dog took 20 minutes because he collapsed so often; he would nibble at a piece of meat and then boom! he'd collapse. This happened over and over again, from the excitement."

After working with dogs, which Mignot really likes (he has a dachshund of his own), he is finding it difficult to deal with the two creatures, mice and zebrafish, that he has recently begun to study. Fellow sleep researcher Masashi Yanagisawa, of the University of Texas Southwestern Medical Center at Dallas, sent Mignot some narcoleptic mice, but they spend so much of their day and night sleeping that "we can't really see cataplexy," Mignot says. "We can't tell why they collapse. Are they just falling asleep very quickly, or are they paralyzed but awake?"

By contrast, when a dog has an attack of cataplexy, "it will track food with its eyes even though it can't move about, so you can see the dog is awake and excited," Mignot says. "But with mice, it's hard to tell. We can't see their emotions. And there is no clear trigger—it seems to be just random events."

What about zebrafish? "We're just breeding them now," says Mignot. "We don't yet have any narcoleptic zebrafish. But we did find hypocretin in their brains, and our hopes are high."

—Maya Pines

Photo: Grant Delin

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Reprinted from the HHMI Bulletin,
March 2003, pages 8-13.
©2003 Howard Hughes Medical Institute