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Mind Games

Memory is our brain’s library, the key to our consciousness and identity. Its loss may be triggered by obesity, head injury, even traffic pollution. Can fasting help?

By Pamela J. Johnson
December 18, 2012

Every person has perhaps billions of bytes of information stored in long-term memory. Babies develop long-term memories for past experiences beginning at the age of about six months or even earlier.

Every person has perhaps billions of bytes of information stored in long-term memory. Babies develop long-term memories for past experiences beginning at the age of about six months or even earlier.

As a child, how many of you memorized the planet names and order with this little ditty: My very elegant mother just sat upon nine porcupines.

Although the demotion of Pluto to a dwarf planet renders this particular mnemonic device obsolete, people have used catchphrases and wordplay to trigger memory since antiquity.

Argue may have lost an “E” in this argument, but University Professor Emeritus Richard Thompson knows only one “C” is necessary and you need two “Cs” for success.

Thompson, William M. Keck Chair Emeritus in Psychology and Biological Sciences in USC Dornsife, has studied learning and memory for more than 60 years. He discovered the essential role of the cerebellum in memory and was the first to localize the site of a memory trace — or the physical storage of memory in the brain.

“Without memory, you would not have a mind,” Thompson said. “If you couldn’t remember anything, ever, you couldn’t think. You couldn’t perceive. Memory is what glues together our experiences as human beings.”

A National Academy of Sciences member, Thompson tracked the minute physical changes that occur in the brain as learning takes place and memories are coded, stored and retrieved. He and his team discovered that the brain encodes a memory by changing the physical structure of connections between neurons called synapses. When something new is learned, neurons sprout new synapses and strengthen existing connections.

Bucking traditional thought, his research showed that memories reside in very specific brain cells and simply by reactivating these cells by physical means, such as light, an entire memory can be recalled.

Memory: The Key to Consciousness (Joseph Henry Press, 2005), which Thompson wrote with Stephen Madigan, associate professor of psychology in USC Dornsife, gives readers a few tips on how to use associations to improve recollection. One he calls “the mind’s eye technique.”

Say you want to memorize a grocery list. Imagine you are walking (or riding your bicycle) down a very familiar path.

“And you envision several weird objects along the path, like a 10-foot-tall tube of toothpaste,” Thompson said. “When you have all those objects really well-remembered, you’re developing a long complicated story of your journey through this path. Then you can take any list of items and tag them on to each object. So in this case, broccoli flower heads are growing out of the giant toothpaste tube.”

Breaking information into manageable pieces, mnemonic devices work because they connect prior knowledge to new knowledge, helping the brain to make sense of information it has never been exposed to.

In the book, Thompson devotes a chapter to the topic of false memory, addressing why some people remember things that did not occur.

Fundamental Misunderstanding

Thompson begins by describing cognitive psychologist Elizabeth Loftus’ 1974 experiments that show what happens to a subject’s memory when he or she is presented with false information.

In one experiment, volunteers watched a short film depicting a collision between two cars. Some were asked, “About how fast were the cars going when they hit each other?” Another group was asked, “About how fast were the cars going when they smashed into each other?” The control group was not asked a question.

A week later, all volunteers were asked if they had seen broken glass at the accident scene. Of the control group, 6 percent said they had and 7 percent of the hit subjects said they had, compared to 16 percent of the smashed into subjects who said they remembered seeing broken glass.

The words researchers used to describe the accident greatly affected what the subjects said they saw in the film. Loftus’ research has relevance to legal issues, particularly when it comes to asking accusers leading questions.

Take cases involving childhood sexual abuse allegations. Thompson describes a 1994 case in Wenatchee, Wash., in which a young foster daughter of a police officer said she and her classmates had been sexually molested. Some children described outlandish acts at a church involving men dressed all in black and wearing sunglasses.

Without physical evidence, the claims led to the arrests of more than 40 people and the convictions of some.

Equally astounding are cases of recovered memory in adults with multiple personality disorder (MPD), which some psychologists say is a result of a traumatic experience in childhood, usually involving sexual abuse. The person with MPD is said to adopt a new personality to cope with emotional suffering. The new personalities are accompanied by a complete repression of memories of the abuse, some say.

Many psychologists argue that the recovered memory issue is a result of a fundamental misunderstanding about the mechanisms of memory.

One wrong belief is that memory is a high-resolution recording device that creates a continuous, detailed copy of experience from which memories can be “played back” with perfect fidelity. Although people are capable of extensive visual and auditory long-term memory, there is no “videorecorder” model of memory, Thompson wrote.

Another mistaken belief is that there is a memory process known as repression — unconsciously motivated forgetting — that is capable of removing memories, even repeated experiences, from the consciousness. Thompson wrote that to date, none of the numerous experimental studies of emotion, memory and the brain have led to the identification of biological plausible brain mechanisms that would be required for repression to operate.

 


The most basic mnemonic technique involves forming a mental image of each of the things to be remembered as occupying a place along a travel route you know well. When you need to retrieve the information, take a mental stroll along the route.

Memory Cache

Thompson’s greatest legacy is his research on the mechanism of memory storage, where and how the brain stores memories. Working memory — or short-term memory concerned with the immediate task at hand — occurs in the prefrontal cortex; long-term memory is kept in the hippocampus; and skill memory in the cerebellum.

“We think this is just the beginning,” Thompson said. “We think that many aspects of memory can be highly localized. We just haven’t found them all yet. Our memory trace was the first.”

After localizing the memory, scientists can learn how each memory is formed — thus understanding the neurobasis of the many kinds of memory.

“You can’t analyze the mechanisms of memories until you find out where they are,” Thompson said. “In the long run, this research will provide ways for treating learning disabilities and memory diseases. And there are many.

“Maybe, just maybe, this work will lead to the ultimate prevention and treatment of Alzheimer’s disease.”

Some of Thompson and his team’s latest research demonstrates that allopregnanolone, a naturally occurring steroid produced in the central nervous system, increases the number of neural stem cells and restores cognitive function in the Alzheimer-inflicted mouse brain.

The research advances the development of allopregnanolone as a therapeutic to restore cognitive function in people suffering from Alzheimer’s.

Published online in the Proceedings of the National Academy of Sciences, the study — co-authored with Roberta Diaz Brinton, who holds the R. Pete Vanderveen Chair in Therapeutic Discovery and Development in the USC School of Pharmacy, and others — has led to planned clinical trials in humans.

Although encouraging, Thompson said allopregnanolone is likely not the ultimate way to fight the disease.

“I think the ultimate answer is manipulating the human genome,” Thompson said. “You would want to do it before Alzheimer’s has developed. That’s in the future.”

Healthy Heart, Healthy Brain

While investigating the causes of Alzheimer’s disease, Margaret Gatz, professor of psychology, gerontology and preventive medicine in USC Dornsife, has studied the health of more than 14,000 Swedish twins for more than 25 years. 

Alzheimer’s is a type of dementia. Dementia is a term used to describe a wide range of symptoms associated with memory impairment and other thinking skills. Alzheimer’s disease, which involves a particular set of changes in the brain that very gradually steal away a person’s memory, accounts for up to 80 percent of dementia cases.

In her twins study, Gatz determined that about 70 percent of risk for Alzheimer’s disease is due to genetic causes. In each stricken individual, the cause is a combination of genes and environmental influences. By studying cases in which one twin developed Alzheimer’s disease and the other twin did not, her team found that midlife type 2 diabetes and obesity are significant risk factors for Alzheimer’s. Those who have the onset of diabetes in midlife have more than twice the chance to develop the disease compared to twins with no history of diabetes.

“This leads to a concern with the obesity epidemic in the United States and worldwide that, in fact, obesity may play out in creating greater risk for dementia in the decades to come,” Gatz said. “So there’s a longer term reason to worry about carrying too much weight — your cognitive health.”

 Speaking to people in the community, Gatz has found that the connection between a healthy heart and a healthy brain is not well known.

“But it’s clearly there,” said Gatz, chair of USC Dornsife’s Department of Psychology and adjunct professor at the Karolinska Institutet in Stockholm, Sweden.

As director of the education core at the USC Memory and Aging Center, Gatz helped to create a comic book-style novella in Spanish and English called Forgotten Memories, which shows community members how to recognize signs of dementia. The novella targets the Latino community because Latinos have a high prevalence of diabetes and other vascular risks.

Her twins research discovered other risk factors.

 


An Alzheimer patient’s damaged brain cells are filled with neurofibrillary tangles, aggregates of the hyperphosphorylated tau that is now known as the primary marker of the disease.

Cancer and Cognition

In a 2005 study published in the Journal of the National Cancer Institute, Gatz and Beth Meyerowitz, professor of psychology in USC Dornsife, and their team of students determined that cancer survivors are twice as likely to develop long-term cognitive problems including memory impairment than those who have never had cancer.

Research has shown that cognitive impairment in cancer patients can persist even five years after treatment. But how long these cognitive deficits last or whether they worsen and become more apparent in older age has been a question.

Seeking to determine the extent of cognitive deficits in cancer patients, the team conducted a study of 702 cancer survivors from Sweden and their cancer-free twins using data collected through the Karolinska Institutet.

They found that those who had survived cancer for five or more years were twice as likely as their cancer-free twins to have cognitive dysfunction — assessed during standardized, mental-status telephone interviews.

Participants were scored on a scale from zero to three. Anyone who scored a three, defined as having verbal, orientation or recall problems that interfere with daily life, was considered to have cognitive dysfunction.

“The twin who had cancer was more likely to have some sort of cognitive dysfunction,” said Meyerowitz, vice provost for faculty affairs.

Previous studies had found cognitive problems in short-term cancer survivors, but this was the first to find significant cognitive differences between long-term survivors and cancer-free individuals, and to focus on older adult survivors.

“This suggests that possibly the cognitive dysfunction gets worse over time with increased survival duration,” said the study’s lead author Lara Heflin, who in 2007 earned a Ph.D. in psychology in USC Dornsife and completed postdoctoral research at the University of California, San Francisco Medical Center.

The comparison with cancer-free twins means that the increased dysfunction cannot be attributed to the normal aging process.

Cancer survivors were also twice as likely to be diagnosed with dementia, although this result was not statistically significant. The authors concluded that cancer and its treatments may lower survivors’ cognitive reserve, thus increasing their long-term risks of cognitive dysfunction and dementia.

“This is a serious clinical concern for physicians treating cancer survivors,” Heflin said. “Further research should identify mechanisms that mediate the relationship between cancer and cognitive dysfunction and explore whether specific treatments are associated with long-term cognitive effects. This knowledge will help health care providers and patients make informed decisions about treatments.”

In a recent study published in The Journals of Gerontology, Gatz, Meyerowitz and their team found that older female cancer survivors are significantly more likely to suffer from long-term cognitive impairment. Compared to those with other cancers, the risk was higher among survivors of gynecologic cancers and those who had treatments potentially affecting ovarian functioning.

The researchers initially thought chemotherapy might be associated with cognitive impairment. Instead, researchers found the impairment was linked to treatments that may have affected ovarian functioning, which likely resulted in declines in estrogen levels. Although most in the study were past menopause, the loss of estrogen may have affected their cognitive performance.

The study raises the question that the loss of estrogen, even in older women, may be associated with memory function — which appears to differ from other highly publicized studies that claim giving estrogen therapy to women increases their risk of dementia.

“I think it may be important to look at how and when estrogen levels are changed through surgery or estrogen therapy,” said Keiko Kurita, a psychology Ph.D. student and lead author of the Journals of Gerontology cancer study, referring to the seemingly contradictory findings.

Kurita, who is pursuing a dual master of public health degree at Keck School of Medicine of USC, is writing her dissertation on the association between the removal of ovaries —  which produce estrogen  —  before or after menopause, and cognitive functioning in older adult women.

“By examining the effects of ovarian removal, we may have a better understanding of the association between estrogen decrease resulting from a surgical procedure and cognitive functioning,” Kurita said. “To the extent that estrogen decrease results in poorer cognitive function including memory loss, there may be implications for treatments that involve prophylactic ovarian removal or that replace the function of estrogen.”

Gatz also pointed to brain injury as a risk factor for later developing dementia as well as other neurological diseases. It’s not only severe brain injuries that predispose people to dementia. A concussion or mild brain trauma can put a person at risk, Gatz said. Soldiers, boxers, athletes and cyclists are most prone.

“So there’s another reason to wear a bicycle helmet,” Gatz said.

There are so many different genes and risk factors that Gatz is dubious there will be one single cure or one single recipe for prevention.

“You want to do something good to reduce your chances of dementia and memory loss?” Gatz said. “Hop on a treadmill.”

Plaques and Tangles

Another leading scholar in the investigation of Alzheimer’s disease is University Professor Antonio Damasio, who holds the David Dornsife Chair in Neuroscience and is professor of psychology and neurology. In the ’80s, Damasio led a number of crucial studies mapping the distribution of damaged cells and neurons in the brain that correlated with Alzheimer’s disease.

The paper that launched a series of studies was published in Science in 1984, when Damasio was professor and head of neurology at the University of Iowa. The paper marked the first time scientists were able to show how the hippocampus — located in the medial temporal lobe — becomes isolated and taken off line by Alzheimer’s-damaged cells in another part of the temporal lobe — the entorhinal cortex.

In a paper published in the journal Cerebral Cortex in 1991, Damasio and his team mapped Alzheimer’s patients’ damaged brain cells that were filled with neurofibrillary tangles, aggregates of the hyperphosphorylated tau that is now known as the primary marker of Alzheimer’s.

“Tau proteins are extremely important because they damage the neurons themselves as opposed to damaging the environment of the neurons,” Damasio said.

They also mapped in brains another characteristic of Alzheimer’s disease, the accumulation of amyloid plaques between nerve cells, or neurons. Amyloid is a general term for protein fragments that the body produces normally. As people susceptible to Alzheimer’s grow older, their cells produce a much higher percentage of amyloid, leading to its accumulation and formation of hard, insoluble plaques.

Damasio, founder and director of the USC Brain and Creativity Institute, housed in USC Dornsife, is most famous for finding the neural basis for emotions and showing that emotions play a central role in decision-making and social cognition — or the processes we use to understand the world around us.

Emotions can have both a positive and a detrimental effect on memory, Damasio said.

“It depends on the amount of emotion,” Damasio said. “Positive emotion can help you learn things very well — to a point. When you are overjoyed you can actually get distracted and learn less.”

Negative emotion can be helpful as well. When a person becomes emotional as a result of being in pain, “that gets your attention and actually may make you learn much better,” Damasio said.

“Let’s say you burn yourself,” he continued. “You learn very quickly not to go to the place where you burned yourself. However, if the pain is excruciating and you are in immense suffering, you may lose the gains that the emotion gives. So emotion, positive or negative, can be a positive influence on learning and memory, but beyond a certain point you actually have diminishing returns.”

A bit of stress and anxiety can increase one’s memory, he said.

“But too much suffering may actually block the availability of the memories you create. You end up not knowing what you learned.”

 


Frequent exposure to toxic fumes and particles that emanate from traffic may affect brain neurons, raising the possibility of long-term health consequences, including the loss of memory.

Brain Gridlock

External factors, such as high urban pollution, can also adversely affect memory, said University Professor Caleb Finch, an expert on the aging process. In a 2011 study published in Environmental Health Perspectives, Finch and his authors showed that freeway pollution affects brain neurons, raising the possibility of long-term brain health consequences.

Many studies have drawn a link between vehicle pollution and pulmonary and cardiovascular problems, but Finch was the first to explore the physical effect of freeway pollution — particles from burning fossil fuels — on brain cells.

“For example, people who live along the 405 or 101 and other urban freeways are exposed to a river of toxic fumes and particles that come off of traffic,” said Finch, holder of the ARCO/William F. Kieschnick Chair in the Neurobiology of Aging in USC Dornsife and the USC Davis School of Gerontology.

“That’s a fact of urban life. We found that in mouse models nanoparticles from freeway traffic accelerate the rate of brain aging and may accelerate Alzheimer’s disease.”

In 1984, Finch founded the USC Alzheimer Disease Research Center and was its director for 20 years. He’s now co-director.

In 2009, with an award from USC’s James H. Zumberge Research and Innovation Fund and support from the provost’s office, he also helped to create the USC AirPollBrain Group, a network involving five USC schools (USC Dornsife, gerontology, engineering, pharmacy and medicine). The group researches the effects of environmental pollution on the brain from conception across a lifespan.

Using technology developed by Constantinos Sioutas of USC Viterbi School of Engineering, Finch and his team recreated air filled with freeway particulate matter and found that in live mice and mice brain cells in vitro, neurons involved in learning and memory showed significant damage.

The nanoparticles in the experiment were minuscule — roughly one-thousandth the width of a human hair, much too small to be trapped by car filtration systems. The mice were exposed for 150 hours over 10 weeks, in three sessions per week lasting at least five hours each.

In contrast, frequent commuters are exposed to smoggy freeway air over a longer period than the mice were in the study.

How can urban dwellers and drivers be protected from this type of toxicity?

“That’s a huge unknown,” Finch said.

Electric cars would not solve the problem on their own, Finch said. They do sharply decrease the local concentration of nanoparticles, but currently electrical generation depends upon other combustion processes — coal — that in a larger environment contribute nanoparticles anyway.

“Reducing the amount of nanoparticles around the world is a long-term global project,” Finch said. “Whether we clean up our cars, we still have to clean up our power generation.”

Finch’s book, The Biology of Human Longevity: Inflammation, Nutrition and Aging in the Evolution of Life Spans (Elsevier Inc., 2007), addresses chronic inflammation as a major cause of several fatal degenerative diseases, including Alzheimer’s.

Typically, inflammation — redness and swelling — is part of a healthy immune response, a surge of cells and chemicals that heal injury and fight infection. But the process also has a silent, dangerous side. Chronic inflammation occurs throughout the body when something activates the immune system and disengages the shut-off button.

Inflammation can be sparked by repeated or prolonged infections, smoking, gum disease or obesity — fat cells churn out inflammatory proteins called cytokines. The end result is the same: An endless stream of immune cells interferes with the body’s healthy tissues, triggering genetic mutations that can lead to cancer, the bursting of plaque in an artery wall or Alzheimer’s.

“We’re trying to find out what aspects of inflammation during Alzheimer’s are therapeutic targets,” Finch said. “There are some aspects of inflammation in the brain that are beneficial because it removes toxic proteins; other aspects cause further damage to neurons.”

Those processes can coexist, he added.

“I’m not running a drug development lab, but we’re trying to figure out therapeutic approaches. In the field generally, we’re trying to identify which processes of inflammation and Alzheimer’s disease are amenable to particular drugs.”

In combating Alzheimer’s, scientists are trying to remove the amyloid protein, one of the sources of the toxic process.

“We as a field are trying to develop immunotherapy; making antibodies that get into the brain and remove the amyloid — the bad stuff,” Finch said.

Empty Stomach, Full Mind?

One of Finch’s former postdoctoral researchers is Valter Longo, now professor of biological sciences in USC Dornsife and gerontology at the USC Davis School of Gerontology. Longo, Edna Jones Chair of Biogerontology, studies the mechanisms of aging in organisms from yeast to humans.

Working with Ecuadorian endocrinologist Jaime Guevara-Aguirre, in collaboration with the Keck School of Medicine of USC and other partners, Longo conducted a 22-year study published in Science Translational Medicine in 2011 suggesting that a growth-stunting mutation may thwart cancer and diabetes.

The group is studying Ecuadorians with Laron-type dwarfism, a deficiency in a gene preventing the body from using growth hormones. The study team followed about 100 such individuals and 1,600 relatives of normal stature. Researchers found that none of the community members with the gene mutation developed diabetes — though they had a high rate of obesity — and only one developed cancer, albeit a nonlethal form.

Now, the team is testing the hypothesis that the gene mutation leading to dwarfism may protect against dementia and Alzheimer’s. Longo’s laboratory is involved in clinical studies to determine whether people with Laron syndrome are protected from age-dependent cognitive decline. The Longo laboratory hopes to eventually use growth hormone-blocking drugs such as pegvisomant to prevent age-related diseases.

Artificial hormone blocking, however, is not the only way to halt the hormone receptor in humans. Restriction of calories or of specific components in food such as proteins appears to have the same effect.

Longo’s team is assessing the effect of dietary restriction in humans and other primates. A recent study by Longo’s group showed that fasting induces rapid changes in growth factors similar to those caused by the Laron mutation.

But fasting or restricting particular nutrients for long periods can lead to dangerous conditions, including anorexia and reduced blood pressure. Also, people with rare genetic mutations can suffer life-threatening effects from even short periods of fasting. Longo emphasized that additional studies are needed and that any changes in diet must be approved and monitored by a physician.

However, short periods, say four days per month, may be beneficial, Longo said.

“In terms of endangering somebody, it’s very unlikely that could happen after four days of fasting,” said Longo, referring to people in excellent health. “All evidence so far indicates it’s healthy, but we’re doing a tremendous amount of work to make sure that it is. But it takes time. Whereas with cancer we’ve done an abundance of work already, with Alzheimer’s we’re just getting started.”

Illustrations by Anna and Elena Balbusso

Read about the neural circuit in a songbird's brain that encodes learned vocal sounds >

Read more articles from the Fall 2012/Winter 2013 issue of USC Dornsife Magazine