Study Illuminates Brain's Ability To "Rewire" Itself After Strokes Or Injuries
Source:Vanderbilt University Medical Center
NASHVILLE, Tenn. - The adult brain appears to have a surprisingly strong built-in capacity for change, a study by Vanderbilt University researchers suggests, creating the possibility for innovative treatments for brain disorders.
The seemingly limited ability of the adult brain to recover from stroke or accidental injury has been a major stumbling block in treating brain disorders. However, the Vanderbilt study showed new growth in cell connections following injury.
Writing in the Nov. 6 edition of Science magazine, three Vanderbilt University researchers report that cells in the adult brain can sprout new axons, or branches, that travel relatively long distances and make contact with new targets at distant sites in the brain. The new growth was found in a region of the brain called the sensory cortex that receives information from touch.
First, the normal connections among cells in the sensory cortex were studied by injecting a harmless substance that reveals or "labels" cells and makes it possible to trace the point-to-point nature of cell connections, according to Sherre Florence, research assistant professor of psychology at Vanderbilt.
She said that cells in the sensory cortex normally have specific connections with neighboring cells. For example, cells that receive information from the hand make connections only with other cells concerned with the hand.
However, in four monkeys with hand injuries, cells had connections that spanned a much wider area of the sensory cortex, a nearly twofold increase compared to normal monkeys.
"Cells within the injured hand cortex apparently grew connections into neighboring cortical zones that were unimpaired by the injury," Florence said. "And cells outside the hand region of cortex made connections to cells in the zone deprived of sensory information because of the hand injury."
According to Florence, the way the cells behaved within the zone of expanded connections changed, suggesting that the new connections made fully effective contacts with their new targets. This could give the new connections the opportunity to change brain function.
The new growth appeared to be triggered by the injury to the hand. None of the injuries directly impacted the brain, but they all had the common effect of disrupting the amount and pattern of activity being relayed to the brain from the hand.
Florence and her colleagues think that it was the massive change in activity patterns that initiated the chain of events that led to new cell growth, not the injury itself. This suggests that it may be possible to coax more flexibility out of the adult brain, taking advantage of these natural processes, in contrast to other lines of research where chemicals were administered to facilitate cell growth.
The ultimate goal is to be able to reproduce the conditions necessary for axon growth, to help cells in the adult brain form effective new long-distance connections.
This might make it possible to reverse some of the effects of damage to the nervous system from spinal cord injury or brain disorders such as stroke.
Scientists Identify Brain Regions Where Nicotine Affects Attention, Other Cognitive Skills
Source:NIH/National Institute On Drug Abuse
Nicotine administration in humans is known to sharpen attention and to slightly enhance memory. Now scientists, using functional magnetic resonance imaging (MRI), have identified those areas of the brain where nicotine exerts its effects on cognitive skills.
Their findings suggest that nicotine improves attention in smokers by enhancing activation in the posterior cortical and subcortical regions of the brain--areas traditionally associated with visual attention, arousal, and motor activation. This study provides the first evidence that nicotine-induced enhancement of parietal cortex activation is associated with improved attention.
The investigators used functional MRI to visualize nicotine's effects on the brain during a rapid visual information-processing (RVIP) task -- a task that requires sustained attention and working memory. Fifteen smokers with and without a 21- mg transdermal nicotine patch performed the RVIP task while undergoing MRI screening. The subjects performed the RVIP task twice--once with a placebo patch and once with a nicotine patch--and were scanned during each session. They smoked their last cigarette 15 minutes before performing the RVIP task.
When smokers were given a placebo patch for the first scan and a nicotine patch for the second scan, there was improvement in task performance between the two scans. When smokers were given a nicotine patch for the first scan and a placebo patch for the second scan, there was no difference in their performance, suggesting that nicotine and practice interact.
Study findings also suggest that nicotine helps focus attention on task demands by shifting cognitive resources from less "used" parts of the brain to regions required for task performance.
WHAT IT MEANS: This study adds to the understanding of the effects of nicotine on the brain. Such understanding helps explain both nicotine's addictive properties and potential therapeutic applications.
From survival of the fittest to staying fit just to survive: scientists probe the benefits of exercise — and the dangers of sloth.
by Jonathan Shaw
In the bottle before you is a pill, a marvel of modern medicine that will regulate gene transcription throughout your body, helping prevent heart disease, stroke, diabetes, obesity, and 12 kinds of cancer — plus gallstones and diverticulitis. Expect the pill to improve your strength and balance as well as your blood lipid profile. Your bones will become stronger. You'll grow new capillaries in your heart, your skeletal muscles, and your brain, improving blood flow and the delivery of oxygen and nutrients. Your attention span will increase. If you have arthritis, your symptoms will improve. The pill will help you regulate your appetite and you'll probably find you prefer healthier foods. You'll feel better, younger even, and you will test younger according to a variety of physiologic measures. Your blood volume will increase, and you'll burn fats better. Even your immune system will be stimulated. There is just one catch.
There's no such pill. The prescription is exercise.
"We've spent years studying numerous nutritional and lifestyle factors," says Frank Hu, associate professor of nutrition and epidemiology at the Harvard School of Public Health (SPH). "Good nutrition is essential for health," but once-promising discoveries, including antioxidant supplements like beta-carotene, have turned out not to be magic pills. "The single thing that comes close to a magic bullet, in terms of its strong and universal benefits, is exercise."
During the last 10 years, epidemiologists like Hu have clearly demonstrated exercise's protective effects against many serious diseases. And yet, as one medical researcher studying exercise in elderly populations put it, "Exercise is often overlooked." Though a large body of epidemiological research shows its protective effects against numerous maladies, there has been less research into how these effects actually take place. Exercise can change virtually every tissue in the body, but because it works by many different pathways — metabolic, hormonal, neurological, and mechanical — understanding why and how it works, in an integrated way, is not easy. We know exercise is good for us. But why?
The Sedentary American
Seventy-five percent of the population of the United States fails to meet even the minimum government recommendation for daily exercise: 30 minutes of walking or its equivalent, accumulated in bouts as short as 8 to 10 minutes. The recommendations have in some ways become easier over the last three decades (see "Exercise: A Changing Prescription"), but we have given up physical activity of any kind even faster.
"America loves to think of itself as a youthful nation focused on fitness, but behind the vivid media images of robust runners, Olympic Dream Teams, and rugged mountain bikers is the troubling reality of a generation of young people that is, in large measure, inactive, unfit, and increasingly overweight." So begins Promoting Better Health, a Centers for Disease Control (CDC) report. "Walking and bicycling by children aged 5 to 15 dropped 40 percent between 1977 and 1995," it continues. Even in schools, budget constraints have led to suspension of physical education classes. Steven Gortmaker, professor of society, human development, and health at SPH, and colleagues recently used a tracking device to measure the minute-by minute physical activity of school-age children throughout the day. The highest levels of activity, he told a group of public-health professionals at an October 2003 seminar on the "Worldwide Childhood Obesity Epidemic," occur during the hours when children travel to and from school. Since 1980, the percentage of American children who are overweight has doubled.
In 2003, the CDC declared obesity the most important public-health issue in the United States. Obesity increases the risk for type 2 diabetes, cardiovascular disease, and some cancers. Two-thirds of Americans are now overweight or obese. In Michigan, half the men are overweight — 34 pounds on average — and the problem has been steadily growing for more than 25 years. Children and teenagers are contracting "adult-onset" diabetes at a rapidly increasing pace. As Dr. Kenneth Cooper, M.P.H. '62, one of the country's foremost experts on physical activity (he coined the word aerobics) puts it, "In Texas, we may have the first generation in which the parents will outlive their kids," as obese children who develop diabetes before 14 years of age can expect their lifespan to be reduced by 17 to 29 years.
This epidemic is not confined to any particular region of the United States. It is ubiquitous, Gortmaker says, in rural and urban communities, among both the wealthy and the poor.
The cause? Epidemiologists call it an energy imbalance: too much food and too little activity.
The imbalance is small, equivalent to the caloric content of one sugar-sweetened drink per day, Gortmaker says, suggesting that giving that up, or forgoing a few bites at dinner, could prevent further weight gain. Soda, fast food, and the super-sizing of portions are frequently cited as culprits on the intake side of the equation, because a typical fast-food meal (double cheeseburger, soda, fries, and a dessert) can contain, at 2,200 kilocalories, enough energy to power a 120-pound person through an entire marathon. Even so, by some estimates, this country's per capita caloric intake in the last 20 years has not increased enough to account for the increased body mass in the same period. For that, we have to look to other changes in lifestyle.
"Obviously, there is no longer any need for physical activity for transportation, food-seeking, or daily survival," says JoAnn Manson, M.D., chief of preventive medicine at Brigham and Women's Hospital in Boston and a professor at SPH and Harvard Medical School (HMS). "We have labor-saving devices everywhere. You can get through the day expending virtually no energy, doing virtually no physical activity. Many people do choose that lifestyle."
The modern lifestyle is a radical departure from the one in which we evolved. Though scholars disagree on the relative amount of time that our hunter-gatherer ancestors spent running versus walking, the evidence suggests that they covered a lot of ground either way: 10 to 20 kilometers a day walking among men, says professor of biological anthropology Richard Wrangham, "and about half that for women. Chimpanzees, by comparison, walk only 2 to 4 kilometers a day, and all other apes walk even less. The ordinary thought," he says, "is that women would have done this every day, because they would have been the providers of the staple foods." Activity levels were probably more variable with men: "[They] would have been bringing in the more chancy foods as well as relaxing after a particularly heavy day the day before." Wrangham's colleague, professor of anthropology Daniel Lieberman, thinks running has long played an important role in human societies. He points not only to anthropological evidence (the running traditions of Native Americans, for example), but also to a host of musculoskeletal adaptations that he says can only be explained as adaptations for running, such as the Achilles tendon, which "has no function in walking, is absent in chimpanzees, and first appears in the genus Homo." Either way, the human record tells a story of frequent, long distance, aerobic exercise.
Epidemiologists debate the merits of walking versus running, but agree that studies link increasing activity levels to better health along a continuum ranging from extreme sedentary behaviors to the "vigorous exercise" of subjects who run more than 20 miles a week. Hu believes that in discussions of the benefits of exercise, the extreme low end of the spectrum — sedentary behavior — is too often neglected. Being sedentary is an independent risk factor for coronary heart disease (CHD), notes Manson, even among people who do exercise. "We found in the Women's Health Initiative [a study of more than 160,000 postmenopausal women aged 50 to 79] that the longer you sit each day, the greater your risk of cardiovascular disease, even after you adjust for time spent in recreational activity." She tells her patients to get up and walk around as much as possible, and to reduce screen time (TV, video games, working at the computer). "The key is to minimize sitting," she says. Hu agrees. Given that the average American spends 4 to 5 hours a day watching television, he says, "For most people, it is not sufficient to address only the exercise side of the coin. Equally important is the sedentary side of the coin."
One sedentary behavior in particular has drawn the attention of public-health researchers. In a landmark study that compared watching TV to reading, sitting at a desk, and driving, Hu found that TV watching is far more likely to lead to obesity and diabetes than any of the other sedentary behaviors. First, Hu explains, "when people watch TV, they eat." Second, they tend to make bad food choices: TV watchers eat more junk food and fast food. And when people watch TV, their metabolic rate (the rate at which energy is burned) drops lower than when they sit and read or work on a computer. "The reason is that TV watching is completely passive," says Hu. "It is almost like sleeping — sit back and relax — that's the message." People who watch TV also tend to spend a lot of time at it (women watch at least an hour more per day than men). And so prolonged TV watching — Hu calls it "a major public-health hazard" — displaces other activities that would be better for people's health. Gortmaker, who pioneered studies of television watching among American children (60 percent of whom have a television in the room where they sleep), notes that among youth, time spent watching television is the one behavioral variable most predictive of obesity.
The Case for Physical Activity
An estimated 18 million Americans now have diabetes, a leading cause of heart disease, stroke, blindness, kidney disease, and nerve damage. If current trends continue, the CDC estimates, more than one in three children born in the year 200o will develop diabetes during their lifetime.
Diabetes is a metabolic disorder that leads to excess sugar in the blood. More than 90 percent of diabetes is the type 2, or "adult-onset," form of the disease that can be prevented or delayed by exercise. In type 2 diabetes, cells that normally take up sugar in response to the body's secretion of insulin become "insulin resistant," causing blood-sugar levels to spike. (People with type 1 diabetes are sensitive to insulin, but require injections of the hormone because they have lost the ability to make enough for themselves.)
In the Nurse's Health Study (a large study of female registered nurses begun in 1976 and based at Channing Laboratory, Brigham and Women's Hospital), Hu found that even walking — a moderate-intensity activity — for 30 to 45 minutes per day lowered the risk of developing type 2 diabetes by 30 to 40 percent. "This reduction is remarkable," he says. "There is nothing else that has stronger and quicker effects than physical activity for preventing diabetes."
Walking a half hour to an hour a day lowers a diabetic's risk of dying from heart disease by 40 to 50 percent. A number of drugs are good at controlling blood pressure, he says, "but none of them is as effective as exercise in delaying or preventing cardiovascular complications and preventing deaths among people with diabetes."
Among healthy people, exercise can raise levels of HDL, or "good" cholesterol, improve clotting factors, lower blood pressure, and decrease inflammation. All of these factors, says Hu, reduce the risk of cardiovascular disease: "We have found that both vigorous exercise and walking can substantially reduce the risk of heart attacks and — this was somewhat of a surprise — both kinds of stroke." (Ischemic stroke, caused by insufficient blood flows in the arteries of the brain, is very similar to heart disease. Hemorrhagic stroke occurs when vessels in the brain rupture and bleed.) "Even though their pathophysiology is very different," says Hu, "exercise can decrease the risk of both." Long-term exercise causes the endothelial cells lining the blood vessels to synthesize nitric oxide, a relaxing factor that increases blood flow. People with insufficient nitric oxide in their system are more likely to have stiff blood vessels, hypertension, and other inflammatory factors, he explains. "That's the common pathway leading to both kinds of strokes, and that is why exercise is beneficial in each case."
How much exercise is enough? Some controversy remains about the optimal amount and intensity of exercise required to reap protective benefits against cardiovascular disease. "Some people say you need to do vigorous exercise in order to achieve the benefits," explains Hu. "Others have said that, no matter what kind of exercise you do, if you have the same amount of energy expenditure, you will get the same benefit." Hu thinks that both are probably right. "For the majority of Americans, it is probably not very useful to distinguish moderate- from vigorous-intensity exercise; the highest priority is simply to increase their energy expenditure. No matter what they do," he says, "it is better than sitting on the couch."
Smart Muscle and Cellular Fuel Sensors
When you eat carbohydrates, either simple sugars or starch, both are converted to glucose and your blood-glucose levels rise quickly. Because long-term high blood-sugar levels are not good for your body, brain, or heart, the pancreas immediately responds by secreting the hormone insulin to counter the surge. Insulin decreases blood sugar by signaling skeletal muscles (as opposed to muscles like the heart) to increase their uptake of glucose from the blood, and helps to inhibit the production of new glucose by the liver. In this way, insulin plays an important role in maintaining the proper blood-sugar level.
If you are physically active and lean, your tissues are very sensitive to the effects of insulin, so you need only a small amount to be effective at controlling blood glucose. But if you are obese or sedentary, the muscles and liver are less sensitive to insulin, so that glucose uptake by muscle is reduced and the liver may continue to produce glucose even when your body doesn't need it. Such people are termed "insulin resistant" and tend to have higher blood sugar. Insulin resistance, a component of metabolic syndrome or syndrome X, is present in nearly a quarter of all Americans older than 20, and in 40 percent of those over the age of 60. Many people live with the condition for years without knowing it, until they develop diabetes.
Even for a person with type 2 diabetes, however, a single bout of exercise sends glucose "right into the muscle, and you have increases in glucose uptake that are normal or near normal," says the Joslin Diabetes Center's Dr. Laurie Goodyear, who studies molecular effects of exercise. This suggested to Goodyear and others in the field that even though exercise and insulin can both increase glucose uptake by the muscle, they must work by different mechanisms.
Insulin circulating in the blood normally works by attaching to insulin receptors on the surface of a muscle cell. This activates a complex series of signaling proteins that instruct glucose transporters within the cell to come to the cell membrane, where they pick up blood glucose and carry it into the cell, where it is either stored as glycogen or undergoes numerous reactions that result in the generation of energy.
If you exercise every day, the number of glucose transporters in your muscles increases, making the muscles themselves even more susceptible to the actions of insulin. "This allows less insulin secretion," says Goodyear, "and a better overall regulation of glucose levels in the body." That effect, depending on the type of exercise and the way you eat "could last for 24 to 48 hours after the exercise bout," says Goodyear. "I think this is the fundamental way that exercise can reduce the risk of developing diabetes and can delay the development of diabetes."
A major factor that controls the sensitivity of muscles to the insulin signal is the level of glycogen (stored fuel), she says: "The more you deplete glycogen levels, the more sensitive the muscles will become." Thus, longer and more vigorous activity — jogging for 60 minutes, for example — will have longer-lasting effects on glucose uptake than a short walk.
But the reason exercise works so well in treating people who already have type 2 diabetes has nothing to do with insulin: they already have insulin in the bloodstream, but the muscles don't respond. The current challenge in Goodyear's field, therefore, is to figure out how this separate exercise effect works.
When a muscle contracts, glucose transporters move to the cell membrane — just as they do in the presence of insulin. This suggested to researchers that perhaps exercise activates the same protein-signaling pathways as insulin. Not so, says Goodyear. She and other scientists have since discovered that a molecule called AMP kinase may be a key to the regulation of glucose transport by exercise. The molecule, which is already known to regulate fatty acid oxidation, is now the subject of an "explosion of research," Goodyear says. "It turns out that AMP kinase is probably doing lots of things in the cell besides regulating glucose transport." It may even regulate PGC-1, a gene transcription protein that HMS professor of cell biology Bruce Spiegelman has shown can increase the number of mitochondria (energy-producing structures) in muscle cells, increase fatty acid oxidation, and even induce switches in muscle fiber type — all adaptations to endurance exercise, says Goodyear. For the purposes of glucose transport, AMP kinase acts as a kind of cellular fuel sensor. Pharmaceutical companies are interested in the molecule as a possible drug target — perhaps a first for the field of exercise research.
Despite the possibility of AMP kinase-based medicines for people with diabetes, Goodyear's research has led her to conclude that it is not the only molecule involved in exercise-induced glucose transport. Her laboratory is now searching for another "mystery" signaling protein that may complete our understanding of how exercise improves glucose transport.
Goodyear emphasizes that she is describing just one of the beneficial effects of exercise. "In addition to the metabolic effects," she says, "exercise changes the phenotype [or pattern of gene expression and hence structure] of the muscle in a positive way." When muscle contracts, she says, "It sends some sort of signal to turn on the transcriptional machinery that will increase the expression of proteins promoting better oxidation of fuels, better glucose transport, and decreased muscle fatigue. We all know that when you train, your muscles perform better. Protein synthesis is enhanced. We are trying to find the signals that lead to these beneficial changes in muscle," she says, "but of course there are changes going on throughout the whole body. All the different cells and tissues are affected in some way."
People who engage regularly in vigorous aerobic exercise undergo some remarkable adaptations. Not only will they develop more mitochondria, glucose transporters, and oxidative enzymes in their muscles, they will grow new capillaries in the skeletal muscles, the heart, and the brain. The left ventricle of the heart will grow larger, and pump even more effectively as total blood plasma volume increases. The number of circulating red blood cells will also rise, improving the ability to carry oxygen. Blood pressure will go down, as will the heart rate at rest.
Exercise, it turns out, is particularly useful in treating the mild depression often experienced by elders due to declining function and increasing isolation. "Keeping your heart and body in shape is just a side benefit to exercise's major effects on the brain," asserts John Ratey, an HMS associate clinical professor of psychiatry. "The brain is where all the action is." During exercise, "the increase in cerebral blood flow creates more capillaries, more conduits for blood to flow in the brain. So you are building a reservoir and protecting the brain, in a way, from strokes in the future."
The increase in cerebral blood flow causes many interesting things to happen. Exercise increases production of a growth factor called BDNF, or brain-derived neurotrophic factor. "I call it Miracle-Gro, brain fertilizer," Ratey says, "because it keeps the neurons young and healthy and makes them more ready to connect with each other. It also encourages neurogenesis — the creation of new nerve cells." This may have a cognitive benefit. Studies have shown that older adults with higher levels of cardiorespiratory fitness experience a slower rate of cognitive decline over time.
But exercise does more than just maintain the health of the brain. "In a way, exercise can be thought of as a psychiatrist's dream treatment," says Ratey. "It works on anxiety, on panic disorder, and on stress in general, which has a lot to do with depression. And it generates the release of neurotransmitters — norepinephrine, serotonin, and dopamine — that are very similar to our most important psychiatric medicines. Having a bout of exercise is like taking a little bit of Prozac [an antidepressant and anti-anxiety agent] and a little bit of Ritalin [which boosts the attention system], right where it is supposed to go." He says there are now many studies which show that "exercise is as good or better than some of our antidepressants."
Why? When we move, we have a sense of purpose, of competence, and of accomplishment. "People don't get the fact that our frontal cortex evolved to make us better movers," Ratey points out. "The higher functions — the executive function, thinking, abstraction, and philosophy — all evolved from the moving brain."
"We're animals," he says. "We should be moving."
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