Timothy Salthouse knows the many faces of memory.

By studying people’s cognitive abilities as they age, he seeks a better understanding of how memory—a fickle friend under the best of circumstances—can become an elusive phantom.
Like remembering where you put your car keys.

“If someone can’t remember where they placed their keys, that’s normal,” Salthouse says. “If they’re holding their keys in their hand and don’t know what they are, that’s a problem.”

Bethany Teachman deals with people whose memory presents problems of a different nature.

“I’ve treated people with spider phobia who have not been down in their basement for 10 years because there once was a daddy longlegs down there,” says Teachman. “How do we understand that?”

Cedric Williams is working to answer just that question, but in a different context. By understanding how the brain processes information, particularly if it has a vivid emotional component, he hopes to ease the debilitating effects of traumatic memories.

Salthouse, Teachman and Williams are among the many researchers at the University exploring memory and other cognitive functions. Salthouse examines the effects of aging; Teachman studies social anxieties and phobias; Williams probes neural mechanisms—how hormones trigger pathways in the amygdala, hippocampus, neocortex and elsewhere.

“I think all of us are using different approaches to get at the idea that memory is both phenomenal and fallible,” says Teachman. “We want to understand the ways that it works well for us and the ways it goes awry. And that can happen to lots of different populations for different reasons.”

Memory holds a defining place in our identity. It prompts and compels, fascinates and baffles. And like so many aspects of our nature, it serves us well when it functions smoothly but frustrates us mightily when it fails our needs.

The topic intrigues us enough to generate headlines about current research. “Migraines, Memory Loss: Was It All in His Head?” asks a Washington Post story. “Brain Researchers Open Door to Editing Memory” says the New York Times. “Scientists Give Flies False Memories” reads an article in Science Daily.

The field is a fertile frontier where modern tools—computers and functional magnetic resonance imaging—open new windows. Using fMRI, one group of researchers found that thought patterns used to recall the past are strikingly similar to those used to imagine the future.

In another, researchers scanned the brains of people who had watched short films repeatedly, until the memories were fully encoded, or stored, in the brain. A computer analyzed the scans as the participants recalled the films. Not only could researchers predict which movie was being recalled, but they found that the patterns of brain activity among different participants were “incredibly consistent.”

Stalking the trail of memory

Like many neuroscientists, Cedric Williams, a psychobiologist, wants to understand the mechanics of memory—how emotional reactions triggered by a squirt of adrenaline in the body will drastically improve your recollection of any event. For example, say you’re a motorist who passes a place where you once hit a deer.

“When you drive back past that place, even though there’s no deer, you get this funny feeling,” he says. That feeling is because that stretch of road has triggered a reaction in a particular part of the brain—the amygdala, which is the center for the emotional context of memory.

The amygdala hardly works in isolation. When a driver first hits a deer, there is a jolt of adrenaline from glands in the midsection. That jolt courses up the vagus nerve in the spinal column to the brainstem, where it hits a roadblock—the blood-brain barrier. Too big and bulky to pass, the hormone (adrenaline) triggers release of a chemical neurotransmitter (norepinephrine). The “Hey-I-just-hit-a-deer” transmission goes to the hippocampus, a vital part of the brain’s memory pathway that maintains a record of contexts and places. Somewhat like an old-time telephone operator, the amygdala takes incoming information, analyzes it and often channels it elsewhere with a note saying, “This is important.” In this case, which involves an episode (called an episodic memory), the amygdala has a complex task that involves myriad cognitive functions and coordination with various parts of the brain—hippocampus, prefrontal cortex, cerebellum and others.

Cedric Williams

“Each area encodes separate features of what happened during your experience,” Williams says.

Williams and his team use high-tech tools to trace and isolate specific chemical reactions, down to the cellular level. A process called in vivo microdialysis allows them to collect neurotransmitters from individual brain regions at different points in the learning and memory-encoding process. They have discovered which chemicals initiate and maintain these processes by injecting compounds directly into the brain. “These will either increase the activity of norepinephrine or block the receptors that norepinephrine binds to. These techniques allow us to trace how different areas of the brain communicate with each other,” Williams says.

One practical application is post-traumatic stress disorder. Once a traumatic memory is encoded, triggering the association can cause an emotional overreaction by the amygdala. “If you can suppress specific areas in the amygdala, you can reduce the impact of those memories in re-creating trauma.”

On the other hand, Williams and graduate student Stanley O. King II (Grad ’09, ’11) are looking at what enhances memory and learning. The sensation of novelty, something new and different, heightens awareness and attention. “If you put an animal in a novel situation first and then train him on something, that animal will remember much better.

“We’re tracing the pathways, and what we’re finding out is that the same pathways are involved in memory modulation,” Williams says. Part of his quest is finding the conditions that lead to almost-perfect memory.

The implications of such research—understanding memory and cognitive function to the extent that ideal learning conditions or traumatic emotional reactions can be controlled—are immense. If perfect memory can exist, will everyone have access? If memories can be edited, who controls what you suppress and what you enhance?

Williams sees his role as a discoverer. “With any discovery, there’s going to be evil as well as good, and you just hope that the applications would be used for good.”

The fear factor

Bethany Teachman deals with people who are their own worst enemies when it comes to remembering things, like daddy longlegs in a basement. That’s why she keeps tarantulas in her psychology lab.

Bethany Teachman

Working with former graduate student Shannan Smith-Janik (Grad ’04, ’08), she studied memory bias in highly anxious people, specifically people with spider phobia symptoms. The subjects remembered spider-related words on a list much better when a tarantula was present while they were learning. She also has people handle the tarantulas to help them learn that even though they might feel anxious, the situation is safe.

Another study led Teachman and her team to develop a program that promises practical help for people with social anxieties or phobias. Using computer software, people can be trained to develop more positive associations in memories, ones they otherwise would twist into agonizing fulfillments of their negative self-image. People with social anxiety who had used the program were willing to speak longer when giving an impromptu speech.

In a separate study, people with high social anxiety were compared with those with low anxiety. Everyone gave an impromptu speech; everyone got virtually the same feedback, regardless of how they did; and both groups were asked questions about their speeches immediately and two days later.

Though they look imposing, tarantulas are relatively docile and harmless. Teachman uses them to research fear and learning. In one study, people with spider phobias remembered spider-related words better if a tarantula was present.

The high-anxiety group initially tended to remember the other person’s feedback more positively than they recalled their own and remembered their own feedback as worse (even though the feedback was comparable). Over time, the high-anxiety subjects chewed on the memory, massaging and distorting it. “Socially anxious people are dismissing positive feedback so that they retain their negative self-image and ignore the corrective information,” says Teachman. “They also exaggerate how well others do, and are less likely to dismiss their own negative feedback.”

Teachman says the studies have a common link. “What we’re trying to look at is, what are the cognitive biases and ways of processing information that will help us realize that we’re actually OK in a situation, and even though we feel some anxiety we can cope with it and do OK.”

From spiders to flies

Across the hallway from Jay Hirsh’s office in Gilmer Hall is a doorway marked “Fly Behavior Room.” It smells musty and is pitch dark—he pulls out a special flashlight to move past the dozens of incubators to wooden cases that monitor the movements of fruit flies.

Hirsh, a biology professor, was involved in a study where scientists implanted false memories in fruit flies. Led by Gero Miesenbock of the University of Oxford, the experiment entailed putting flies in a chamber where two distinct odors were introduced from separate areas. Flies in one area received an electric shock and developed a negative association with that smell. They remembered the shock and learned to avoid that area.

The researchers identified 12 neurons in the brain circuit responsible for the memory. Then they exposed the same circuit in fresh flies to a flash of light in conjunction with the odor, triggering a response in those neurons. Though the flies had never been shocked, they avoided the corresponding odor—they had a bad memory of something they’d never experienced.

Miesenbock described his approach as having the ability to “write directly to memory.”

While much remains to be discovered about neural pathways in the brain, specific areas have become associated with storage of and access to certain types of memory. The amygdala, for example, stores emotional memories; the hippocampus, episodic and semantic memory; the cerebellum, procedural memory; the prefrontal cortex, working memory. Information from the internal organs and extremities reaches neural pathways via the brainstem.

Growing neurons

Not so many years ago, scientists believed the brain stopped making new neurons after birth. Now they know neurogenesis continues in adulthood, and researchers like UVA psychologist Brian Wiltgen are probing the role of these new cells in learning and memory.

For example, it’s known that neurons originate in two areas of the brain and migrate to other structures like the hippocampus. “But exactly what these new cells are doing and how they’re involved is not known at all at the moment,” Wiltgen says.

There would seem to be an obvious assumption: more neurons, better learning and memory. So how do you generate more neurons? Previous research has shown correlations between exercise and an enriched environment (lots of mental stimulation) and increased neurogenesis; on the other hand, stress, anxiety and aging appear to decrease it. The evidence is suggestive, Wiltgen says, “but scientifically you really want to nail it, and that hasn’t been done.”

While the influx of new cells might seem great, Wiltgen is looking at an intriguing aspect of that. “New cells don’t have memory. They don’t even have connections. This is a huge problem that people haven’t been able to figure out: How do the hippocampus and the brain deal with this constant influx of new neurons that have to be connected into existing networks. How does that not just screw everything up?”

The older we get

Timothy Salthouse, director of UVA’s Cognitive Aging Laboratory, has led research that suggests memory and other cognitive abilities peak much earlier than we might like. A seven-year study involving 2,000 people between the ages of 18 and 60 found that performance of many cognitive abilities peaked at age 22; average memory declines were detected by about age 37, and things went noticeably south after age 60, even in people otherwise physically healthy.

However, some things—general knowledge, vocabulary improvement, accumulated knowledge skills—actually increased until age 60. Older people learn to accommodate and to solve problems in different ways.

Salthouse notes, however, that there are many moderating factors and individual variances. “That’s really the key,” he says. “There are people who are performing at extremely high levels at all ages. What is it that they are doing, or what is it they inherited, that allows them to age at a different rate than the rest of the people?”

Such questions bear further study, and to that end Salthouse is following hundreds of people, testing them at different ages for memory and a host of other cognitive skills.

“By following individuals over time, we gain insight to cognition changes and may possibly discover ways to alleviate or slow the rate of decline,” he says. “And by better understanding the processes of cognitive impairment, we may become better at predicting the onset of dementias such as Alzheimer’s disease.”

Age also is a factor in a study by UVA psychology professor Chad Dodson and UVA graduate student Lacy Krueger (Col ’09). Older adults tend to make more errors than younger adults in remembering events when details are suggested to them. More than that, they hold to their false memories with great confidence.

Dodson says the devil is in the details older adults believe they remember. “Because the detail seems so sharp, they are highly confident that they are correct in their recollection, even when the recollection has been suggested to them rather than actually witnessed,” he says.

Seeking a sharper edge

It’s safe to say that most people do not want their memory, much less their brain in general, to fail them. In fact, they want to be sharp and will spend big bucks to be so.

Take ginkgo biloba, for example. Americans were spending about $107 million a year on the substance when Dr. Steven DeKosky, dean of the UVA Medical School, released an eight-year study concluding that the flavonoid did not improve cognitive function or prevent dementia.

The rising tide of people seeking memory-boosting drugs led UVA neurologist Dr. Dan Larriviere and other physicians to develop guidelines for prescribing neuroenhancing drugs (stimulants like methylphenidates—think Ritalin—or cholinesterase inhibitors like donepezil) to otherwise healthy patients.

The group advised that patient requests for these drugs should be treated as chief medical complaints, to be examined, discussed with the patient and treated as such. However, there are no legal or ethical barriers to prescribing—or refusing to prescribe—neuroenhancements.

The recommendations led to “a robust debate” among neurologists, Larriviere says. “There are some remarkably high passions on both sides.”

On one level, Larriviere says, the trend raises issues of social justice and economic equity. If an A student just wants to be sharper, that’s different from a C student who wants to be an A student. And one might be able to afford the drugs while the other might not.

He believes requests will become more common, particularly among young adults who have grown up with certain medications. “Ritalin … is well known on college campuses as a ‘study aid,’” says a report in Nature. The journal published results of an informal survey showing that one in five respondents “had used drugs for non-medical reasons to stimulate their focus, concentration or memory.” Stimulant use was highest in people 18-25 years old, with methylphenidate the most popular.

Larriviere says UVA is not immune to such trends, particularly among high-achieving students involved in myriad activities. “If there were four ends of a candle, they would be burning them all.”

A more memorable future?

The 1990s once were proclaimed the decade of the brain. One scribe suggested that the ensuing decade be called the decade of the better brain.

Through the efforts of researchers like Salthouse, Teachman, Wiltgen, Williams and others, the decade ahead promises insights into not only the mechanics of memory but also the practicalities of modulating it and other brain functions.

While the imagination runs wild with possible scenarios, perhaps only one thing can be said with certainty: When it comes to memory and learning, we have much to learn.

Or, as one researcher put it, “In this field, we are merely at the foothills of an enormous mountain range.”