THANKS FOR THE MEMORIES

by Marilyn Davis
 

Why are some memories so vivid,while others fade away? Our vagus nerve is what makes nostalgia possible, SIUC researchers have discovered—and it may offer a way to hasten recovery from brain injury or stroke.
 

If you fondly remember the first time you rode a bicycle without falling down, what you wore your first day to kindergarten, or where you first met the person you married, you can credit emotional arousal—a heightened emotional/physical state. 

Of course, the same applies when you remember the details of certain events you’d prefer to forget—that trip to the ER with your youngest child, say.

Scientists have long known that emotional arousal enhances memory, but they didn’t know exactly how. Adrenaline and other hormones produced when your emotions are engaged have memory-boosting effects—but they don’t readily cross the protective blood-brain barrier. Likewise, certain synthetic drugs improve memory, also without entering the brain. How?

SIUC behavioral neuroscientists and psychology professors Robert Jensen and Douglas Smith have discovered that these agents have their effects via the largest cranial nerve, called the vagus nerve. 

The vagus starts in the brainstem, runs snugly along the carotid arteries, and then snakes through the abdomen, sending feelers out to all the internal organs. It carries messages about the body's physiological state up to the brain—how fast the heart is beating, how quickly the lungs are respiring, and so forth. When the body’s arousal level goes up—whether due to fear or elation, anger or anticipation—those messages somehow cue the brain to make the memory of that moment stronger.

Smith, Jensen, and their students have shown that electrical stimulation of the vagus nerve can improve people’s memory, and hence learning. They’ve also shown that such stimulation can help lab rats recover much more quickly from brain injury—and they expect the same to be true of you or me.

"Part of the recovery of function following brain damage is the ‘learning’ by undamaged areas to take over the functions of the damaged areas," says Jensen. 

In August 2000, he and Smith, along with SIUC physiologist Ron Browning, neurologist Dean Naritoku, former graduate student Kevin Clark, and Reese Terry of Houston-based Cyberonics Inc., were issued a patent for methods of using an electrical nerve implant to improve memory and learning. 

The implant was developed by Cyberonics to suppress seizures in patients with epilepsy by delivering pulses of current to the vagus nerve. The device is being used to treat thousands of people worldwide. Could it also help speed the recovery of people with head injuries or stroke? The SIUC researchers believe that it could.
 

Step by Step

For years, Jensen and Smith have pooled their ideas and their lab teams. That cooperation, Jensen says, "made possible studies that otherwise wouldn’t have happened." Their current understanding of the role of the vagus nerve in memory grew out of several student projects they oversaw that connected with a bang.

Piece #1: In the mid-1980s, graduate student Bob Holdefer found that giving lab rats memory-enhancing drugs boosted neuron firing in a part of the brainstem called the locus coeruleus. Those neurons, which send projections from the locus coeruleus into various parts of the brain, release a neurotransmitter called norepinephrine.

Piece #2: In 1990, graduate student Cedric Williams found that cutting the vagus nerve in rats blocked most of the effects of memory-enhancing drugs that don’t cross the blood-brain barrier. He and Jensen theorized that these drugs triggered signals that were normally carried by the vagus nerve to the brain. When this pathway was severed, the signals could no longer reach their target.

Piece #3: In the early 1990s, graduate student Scott Krahl was investigating why vagus nerve stimulation suppressed seizures in animals—a recent finding by the scientists who had started Cyberonics. Krahl showed that in rats, vagus nerve stimulation caused the neurons in the locus coeruleus to—guess what?—fire more often, releasing norepinephrine. 

"We knew that drugs that cause the release of norepinephrine also tend to have anticonvulsant properties, promote recovery of function following brain damage, and improve memory," says Smith. 

At that point, he adds, "Everything started to come together." The SIUC studies all pointed to the vagus nerve as the means by which arousal strengthens memory in the brain, apparently via the locus coeruleus. 

How would memory be affected, the researchers wondered, if you electrically stimulated the vagus nerve? They thought memory would be enhanced—but there was only one way to know for sure. 

Smith, Krahl, and doctoral student Kevin Clark made and implanted tiny electrodes in rats that wrapped around the vagus nerve. Then they turned on the current, treating the rats periodically (and painlessly) with electrical stimulation.

"And by golly, it worked," says Jensen. Rats receiving stimulation could learn simple behavioral tasks more quickly than rats that didn't. But only stimulation at one intensity range made memory better; higher and lower intensities did nothing.

This parallels what’s known about emotional arousal and memory. A very low level of arousal doesn’t really register. And a very high level of arousal, such as extreme fear, can make memory worse by overloading the circuits. But a moderate level of arousal, whether pleasant or unpleasant, is just right for enhancing memory. 
 

A Stroke of Luck

The next step was serendipity. Jensen and Smith learned that, as part of the FDA approval process, the Cyberonics implant would be tested in epilepsy patients at SIU’s School of Medicine in Springfield. Neurologist Dean Naritoku, who was heading this clinical trial, got Cyberonics’ OK for Jensen and Smith to piggyback a simple experiment onto it: testing the implant’s effect on memory. 

They already knew how to go about it. A graduate student of Jensen’s named Kristy Nielson had previously developed a way to test the effect of arousal on memory. Nielson asked people to read several paragraphs with highlighted words. After reading some of those paragraphs, they squeezed a spring, creating muscle-tension­induced arousal. After reading other paragraphs, they didn’t.

Later, Nielson tested their recall by giving them a list of 250 words and asking them to pick out the ones they remembered having seen highlighted. For both younger and older folks, recall was higher when arousal had been involved.

Kevin Clark borrowed this procedure for the epilepsy patients receiving the implant—except that spring squeezing was replaced by vagus nerve stimulation.

The clinical trial involved testing most patients over three weeks at three different electrical stimulus levels to see which controlled seizures the best. So Clark conducted the experiment three times. Each time, he had the patients read the paragraphs shortly before the implant was turned on. This sequencing eliminated any possibility that nerve stimulation simply tells the brain to pay special attention to what’s coming next. 

Clark discovered that the patients’ recall of the highlighted words improved markedly—about 35 percent—at one and only one level of stimulation (the lowest). Somehow, this mild electrical intensity was helping the brain store and retrieve memories. Clark’s results, published in 1999 in the journal Nature Neuroscience, were widely reported by the news media.

By improving memory and learning, Smith and Jensen reasoned, vagus nerve stimulation might help some of the more than 1 million Americans annually who suffer stroke or serious closed head injury. At the same time, it could help prevent the seizures that so often follow brain injury and delay recovery.
 

Improvising Injury

By sending a pulse of fluid into the brain of an anesthetized rat, researchers can simulate a closed head injury that temporarily impairs motor control and the learning of new tasks. For example, a normal rat running down a narrow beam of wood won’t put a foot wrong; a head-injured rat will make some missteps. 

The injured rats recover on their own in about three weeks. But with vagus nerve stimulation, Smith found, they recover much more quickly, experiencing a surge in functioning even by day 2 of treatment. 

One issue Smith and his students are now addressing is how long they can delay treatment after the injury and still get good results. This will be crucial when medical researchers start looking at brain recovery in humans using nerve implants. 

As Smith points out, doctors might be hesitant to implant such a device right after someone has suffered an accident. How long could treatment wait? The lab studies should give an indication. Working on these projects are two pre-med students, Jeremy Klope and Sarah Turner, who hold Chancellor’s Undergraduate Research Awards; undergraduate psychology student Meghan Fidler; and Rodney Roosevelt, a master’s student in psychology.

Smith also is collaborating with researchers at the University of Miami, who have developed a good method of simulating strokes in rats. "We’ve shown them how to implant the vagus electrodes and agreed on certain behavioral measures [for assessing recovery]," he says. These studies have just begun.

Meanwhile, Jensen and graduate student Tiffanie Markus are investigating another possible benefit of vagus nerve stimulation: reducing anxiety and depression. Epileptic patients who also suffer from depression seem to benefit from the implant, but no one is sure why.

Cyberonics has funded Jensen and Smith’s work for several years. Now, a three-year grant awarded by the National Science Foundation this past summer will allow the researchers to delve deeper into what happens in the brain when the vagus nerve is stimulated. Exactly how does it work to enhance memory?

"To say it’s because the locus coeruleus starts firing more [and releasing more norepinephrine] is like saying your car goes fast because you press the accelerator," says Jensen. "We need to look further."

He and Smith will investigate the role of norepinephrine and will explore the effect of vagus nerve stimulation on two brain structures, the hippocampus and the medial frontal cortex, that are important in memory processes.

Down the road, other avenues in applied research beg to be explored as well. For example, could vagus nerve stimulation help people with Alzheimer’s disease or other memory disorders? It’s a tantalizing thought.

"What you find in one experiment," says Smith, "is the impetus for asking questions in the next."

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