| The Memory Issue | Autumn 2008 |
As Time Goes By Yet, just as our muscles change with age, so, too, do our brains. Small wonder, then, that explorations into how age-related changes affect our brains—and, by extension, the ways we engage with our world—have so captivated researchers, observers, and those who simply hope to keep the old bean keen. Down Memory Lane In 1906, the Spanish anatomist Santiago Ramón y Cajal received a Nobel prize for his “neuron doctrine.” Neurons, he said, function as discrete units. Each cell body receives signals from a rootlike array of dendrites and transmits those signals along an axon to the waiting dendrites of other neurons. Researchers later showed that transmissions from axon to dendrites occur across synapses and that neurotransmitters—substances such as dopamine, acetylcholine, and serotonin—help signals jump these clefts. The idea that neurons form networks that orchestrate our ability to build memories was posited in 1949 by Canadian psychologist Donald Hebb. From his studies of how the brain commanded behavior, Hebb postulated that when one neuron repeatedly caused another neuron to fire, a type of metabolic bonding occurred. His idea spawned a slogan: Neurons that fire together wire together. This fire–wire partnership, researchers later discovered, results in networks of connected neurons, each a memory trace of a learned experience that expands or modifies other traces. When functioning efficiently, the more than 100 billion neurons in the adult brain provide access to a phenomenal cache of information. Researchers have found that it is the degree to which our aging, changing brains construct new connections between these neurons—and avoid or minimize the destruction of existing ones—that determines the scope and vitality of these networks. “The aging process does not appear to be a passive one,” says Bruce Yankner, a professor of pathology and neurology at the Paul F. Glenn Laboratories for the Molecular Biology of Aging at HMS. “It instead appears to be a balance between stress and compensation.” One of the leading theories for how the brain confronts age-related changes is the concept of synaptic plasticity. This theory holds that our brains continually remodel themselves, tweaking the number of connections to other neurons so as to embrace new information, eliminate links to unused networks, and reflect new complexities associated with information in other traces “Synaptic plasticity truly is an exciting concept because it says the brain is not a fixed structure,” says Majid Fotuhi ’97, an assistant professor of neurology at the Johns Hopkins University School of Medicine and director of the Center for Memory and Brain Health at Sinai Hospital’s LifeBridge Health Brain & Spine Institute. “One cell may have a thousand synapses on it but then something happens—you learn something new—and you might then have a thousand and twenty synapses.” Situations that trigger these types of changes occur constantly. Negotiating a reduction of global carbon dioxide emissions, for example, could trigger synaptic growth. So could preparing dinner. Let’s say you use a particular pot regularly. You know it has a small break in the handle, but it’s usable, so you pull it out, fill it with soup, and place it on the stove. After the soup heats, you reach over to pull the pot off the burner. You get burned. A strong signal associated with the pain speeds to your brain, as does the realization that you have touched exposed metal in the handle. Your brain uses this information to establish new connections; you learn to avoid using that pot or to use a potholder when handling it. You have established a memory that, like most memories, helps you function better in your world. Form and Function Viewed without its protective bony outer structure or the rugged inner membrane that wraps its mass of cells, the brain’s cortex bears an uncanny resemblance to a shelled walnut. This wrinkled, bisected structure is arguably the most sophisticated area of the brain. Within each cortical hemisphere is tucked a small structure quite active in memory making: the hippocampus. Shaped like a banana, the hippocampus serves as an active way station for information, holding new material that is needed immediately, sending to storage that which will be held for days or decades, and assisting in the recall of data housed in other cortical areas. The cortex is involved primarily in declarative memory, which captures the facts and events of our lives and allows for their recall in some tangible manner: the spoken word, a visual representation, a gesture. Declarative memory can be held for a short time, as for a one-time use of a telephone number, or it can be held up to a lifetime. And although synaptic plasticity can help keep it robust, biology and environment do conspire to whittle away at it over time. A second form of memory, procedural memory, primarily engages noncortical areas of the brain, most notably the cerebellum. Procedural memory involves sequential, coordinated movements, such as those associated with riding a bicycle. Unlike declarative memory, procedural memory is rugged and not easily lost to the passage of time. This form of memory is a product of action, an imprint of repetitive, serial movements that can be acquired only through physical participation.
Adjusting the Volume Age-related changes to our brains influence the speed with which we can access stored information, the complexity of the neural networks that contribute to those memories, and the level of function of certain cortical areas. The fetal brain produces cells and connections in quantities that far exceed the numbers that will populate the adult brain. As newborns soak up information critical to functioning within their environment, competitive elimination starts to prune away unused or underused cells. Initially, the neurons and synaptic connections, known collectively as gray matter, are focused on taking in information and learning. By six months, however, researchers have found evidence of declarative memory as infants are able to recall one or more steps in a simple sequence of events within 24 hours of having learned them. In another three months, infants can recall isolated steps from a sequenced action after as many as five weeks. By 14 months, babies can recall several steps of a multi-step action for as long as four months while 20-month-olds can recall all the steps—and their proper order—after six months. The robust nature of this progression in behavior mirrors a flurry of development within the structures of the fetal and infant brain. The cells that make up much of the hippocampus form in the first 17 weeks of fetal development and have ordered themselves in the locations they will hold in the adult brain well before birth. Hippocampal synapses also develop quickly; they are present in the fetus by 15 weeks, ramp up their numbers after birth, and reach adult levels by approximately six months. Certain subdivisions of the hippocampus are slower to develop. An area known as the dentate gyrus, important in consolidating new information, has about 70 percent of its adult complement of cells at birth and achieves full adult morphology after 12 months. Synaptic development in this subregion also lags that for the hippocampus: Between 8 and 12 months, the number and density of its synapses spike to a level above that supported during adulthood. By age five, selective pruning has decreased the number of connections to that found in adults. Development in other association areas of the cortex mirrors that of the dentate gyrus. Cortical definition begins around 28 weeks of gestation, with synaptic densities in areas critical to association and storage peaking in infants by age two. Around the same time, the number of synapses in the prefrontal cortex tops out. In the mature brain, this cortical region provides temporary mental workspace, known as working memory, for processing decisions that involve complex behavior and problem solving. Overall, the number and density of synapses most capable of plasticity increase throughout childhood. By age four, however, increases of this gray matter are outpaced by growth in the volume of white matter, the mass of networked neurons whose axons are wrapped in insulating myelin. Myelinated axons propel information up to a hundred times more quickly than their gray matter counterparts, allowing for quicker access and recall of information. In the brain, the period during which its various regions are most actively pruning, myelinating, and maturing—a period of neural growing pains, as it were—coincides with another period known for its awkwardness: adolescence. Gear Up “The cortex of a young person,” says Zaldy Tan, an assistant professor of medicine at HMS and director of the Memory Disorders Clinic at Beth Israel Deaconess Medical Center, “looks like a complicated mass of wrinkled fat tissue, with numerous peaks flanked by valleys. But as the brain ages, its appearance smoothes out; the peaks flatten and the valleys widen.” These topographic alterations are the result of changes to the brain’s volume and cellular material. The ratio of gray matter to white matter begins to shift from age four through early adulthood. Although the precise reason for this has not been found, neuroscientists speculate it may be twofold: an increase in mature, myelinated regions plus the pruning of less productive gray matter synapses. Researchers even have movie-like evidence supporting this conjecture. In time-lapse sequences of gray matter-to-white matter changes, researchers found that the cortical regions in adolescents mature in an order that echoes behavioral progression. First the primary sensorimotor areas along the frontal-to-occipital axis myelinate, then back-to-front myelination occurs from the parietal lobes to the frontal lobes. The prefrontal cortex, that working memory reservoir useful in decision-making, is among the last to mature. Part of that maturation involves an increase in the role of dopamine, a neurotransmitter critical to deciphering environmental cues when choosing between conflicting options. Inputs for this chemical increase significantly during adolescence. Exposure to dopamine is thought to contribute to the development of our ability to use ideas to achieve a goal rather than simply acting instinctively in a given situation. In broad strokes this means an adolescent’s reflexes and keenness of sight and hearing are honed well before the young person’s ability to process complex information is. Even synaptic pruning, which begins in earnest in childhood, changes focus during adolescence. Pruning in the early brain targets low-performing excitatory synapses that transmit information neuron to neuron, a reasonable approach considering the efficiency with which children and early adolescents need to learn. But by late adolescence, pruning zeroes in on inhibitory synapses, which control the flow of information between neurons. Thus, the developing brain grows in its ability to control not only the speed by which signals travel but also the efficiency of their routes. The result: actions grow nuanced so as to, in a sense, reflect a synthesis of information leavened by learning and experience. All this upheaval calms by age 30, when the number of cell-to-cell contacts achieves an adult pattern and the number of neuronal connections reaches a near steady state—except among adults who prod their brains to do more. New Tricks Normal aging in the brain can mean little notable behavioral change for an adult untroubled by trauma to the head, disease that affects the brain, or excessive stresses, whether from responsibility, diet, or lifestyle. Physiological changes do occur—synaptic connections lessen, the volume of certain cortical areas diminishes, and the production of neurotransmitters decreases. Yet the adult brain may actually be able to compensate for these alterations: Some research indicates cortical regions team up to accomplish work previously done individually. Researchers looking at cross-sectional behavioral data for individuals between the ages of 20 and 80 have found little to no evidence for accelerated declines in the latter decades for such capacities as processing speed, working memory, and the encoding of new declarative memories. There is evidence, however, for linear declines in these areas—as well as in spatial ability and reasoning—beginning by age 40 or 50. In one area, speed of processing, several studies have found a 2 percent decline per decade after age 30. “The decrease in speed of mental processing that is seen with age is not a problem,” says Tan. “The brain may become less efficient, but that doesn’t mean it also experiences a decrease in absolute memory.” To tease out secrets to healthy brain aging, Tan is mining a 60-year data trove on the health of another organ: the heart. “Study upon study has shown that physical activity actually decreases one’s risk of cognitive decline with age,” Tan says. “But what has really struck me from my work with the Framingham Heart Study is that healthy aging seems to mean that what’s good for the heartÑa healthful diet, exercise, low cholesterol—is good for the brain, too.” The boost that cognitive health can get from good cardiac health can be augmented by good social health, according to Robert Waldinger ’78, an HMS associate professor of psychiatry and director of The Study of Adult Development at Brigham and Women’s Hospital. “There is strong evidence that people who are more connected to others, whether through marriage, friendships, children, or grandchildren, do better physically, cognitively, and emotionally,” Waldinger says. “Loneliness, in fact, is considered a risk factor for aging poorly.” But with a finely tuned organ such as the brain, little things can mean a lot. Take genes, whose business it is to oversee our molecular world. Several years ago Yankner looked at the genetic signatures of the brains of people whose ages ranged from 26 to 106. He found that certain genes control the formation of new synaptic connections, others respond to age-induced stresses such as the DNA-damaging molecules known as free radicals, and still others are especially vulnerable to DNA damage. An intriguing possibility is that these genetic characteristics may predict the brain’s future. “We found that gene expression was quite similar among young adults under 40 and somewhat similar among adults over 70,” Yankner says. “But those between 40 and 70 showed a good deal of variability—some looked like the young group, some like the older group. This told us that the aging process that determines how you’re going to fare at age 80 probably begins around age 40 or 50.” Reserving Space Barring trauma or illness that would affect brain health, the ability of neurons to ramify remains strong throughout a person’s life. One of the more captivating ongoing investigations of brain health began nearly 20 years ago with a pilot study that looked at healthy aging in residents of a retirement community of Catholic nuns. This largely closed community provided the researchers with a nearly ideal set of participants; the nuns had not only carefully preserved their personal and medical histories but they had also conformed to a documented lifestyle. In addition, the nuns agreed that, after their deaths, their brains would be donated to the study. The investigators explored these precious donations in the hopes of isolating factors that affected the nuns’ cognitive functioning. They found that cognitive capacity was compromised for women whose brains showed signs of cardiovascular disease, such as brain stroke. But they found cognitive function remained strong for women whose brains showed little to no evidence of cardiovascular trauma. Perhaps most interestingly, the researchers also found strong cognitive functioning among stroke-free women whose brains showed moderate to advanced Alzheimer’s disease. Such brains, they speculated, drew upon reserves that delayed or offset the symptoms of dementia. Cognitive reserve—the capacity to sustain brain function and to build effective networks that are less susceptible to disruption, including that which accompanies normal aging or even disease—is a growing concept among neuroscientists. While not exactly a 401(k) for your brain, cognitive reserve acquired from a life of active and sustained learning can keep the brain healthier, longer. “Cognitive reserve is like strength training for your muscles,” Fotuhi says. “When you are fit, you can sustain that fitness for a long period of time. There is compelling evidence that synaptic plasticity continues through age 70 and that brain volume can even increase among healthy adults, especially those who enjoy teasing their brains and exercising regularly. The idea that plasticity exists only in children is completely outdated.” Research on the molecular and physical changes that the brain undergoes with time will likely continue to overturn contemporary ideas of how age, disease, and lifestyle affect our ability to gain, maintain, and recall our individual library of memories. That our brains do alter with age is undeniable. But the lens of research increasingly shows us that when good overall health is maintained and brains are kept agile through learning and challenge, life—and memory—can remain rich for a long time. Ann Marie Menting is associate editor of the Harvard Medical Alumni Bulletin. Photo: ©iStockPhoto.com/Anne de Haas |
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