Now Where Did I Put Those Keys?

Along with ordering their first pair of bifocals and starting to feel the pains of arthritis, baby boomers are now worrying about their memory remember seems to be going in the opposite direction as their need to remember. Are these memory lapses a normal part of growing old, or are they the beginnings of Alzheimer's disease? How can we tell the difference? Is there anything we can do to improve our memory?

Our understanding of the neurobiology of memory has taken gigantic strides in the last five years. We have discovered genes involved in controlling memory. We are testing drugs that may enhance memory. We have scanning technology that enables us to visualize the flow of brain activity at the same time as the subject searches for a memory. And we have even seen changes in nerve cell connections (synapses) in response to learning and experience. These and other recent discoveries promise future treatments to help those having trouble with memory lapses, whether as a result of a degenerative brain disease or just normal aging.

Memories, memories

Memory is not a singular brain function. Rather, the brain processes, stores, and retrieves information in many distinct ways and in many different places. Memories have been classified according to the type of information or the time of retention.

Type of information. Memories categorized by type of information can be either declarative, procedural, or emotional. Declarative memory is the ability to remember names, faces, telephone numbers, or important events. It is material available to the conscious mind, encoded in the cerebral cortex, and expressed by language.

Procedural memory refers to motor activity and skills acquired and retrieved on a subconscious level. We utilize procedural memory during such activities as piano playing, knot tying, and bike riding, when we do not consciously direct our detailed movements. In fact, thinking about the movements may inhibit our ability to perform them. Procedural memories are stored in parts of the brain known as the basal ganglia, the cerebellum, and the premotor cortex.

Emotional memory re-creates our original emotional response. A sight, a sound, or even a smell can bring back the joy, fear, love, or hate that we once associated with it. A buzzing bee or an attractive face may mean little emotionally, until we create memories of being stung or falling in love. The anatomical correlate of emotional memory is the amygdala, located in the temporal lobes on each side of the brain. Destroying the amygdala destroys emotional memory.

If left unchecked, emotional memory can lead to chronic fear, forming the basis of anxiety disorders such as phobias, panic attacks, and post-traumatic stress disorder (PTSD). Normally, the prefrontal cortex dampens the amygdala's response and calms the fear. But for most PTSD sufferers, their prefrontal cortex does not send this message. About 25 percent of Americans have a diagnosable anxiety disorder at some point in their lives, and the collective bill for treating these disorders amounts to about $45 billion per year.

Time of retention. When viewed from the perspective of time of retention, memories may be classified as being part of either working memory or long-term memory. Working memory is the "blackboard" of the brain. It is the capacity to keep information in the conscious mind while performing tasks using that information. It maintains images "on-line" long enough to manipulate them for problem solving and planning. It is similar to a computer's RAM (random access memory). Long-term memory is filed away, stored over extended periods of time, to be retrieved later. It is similar to memory stored on a hard disk drive.

Contrary to popular belief, our brains do not record everything that happens to us. More than 99 percent of the sensory information that enters our bodies is filtered out and does not even reach our consciousness. Most of what does reach consciousness hovers briefly in working memory and then evaporates. Only meaningful experiences are preserved in long-term memory. If we were aware of every sensory message and stored every thought, there would be no room for analyzing, creating, and enjoying.

Losing our memories

Memory loss that accompanies normal aging is primarily a deficit in working memory, due to changes in the prefrontal cortex. It includes absent-mindedness, a shortened attention span, and a decreased ability to hold a thought. This slower, less-precise working memory is a nuisance, but by itself it does not signal the beginning of a degenerative disease, and it is not inevitable. Although memory generally declines with age, some octogenarians retain better working memories than people in their twenties.

Pathological amnesias, on the other hand, differ from regular, age- related memory loss. They occur in either of two main forms: retrograde and anterograde. Retrograde amnesia is the loss of memories of the past. A person who experiences physical trauma to the brain or an electroconvulsive shock may forget his past while retaining the ability to create new memories.

Most of us and Hollywood associate the term amnesia with this form, although its occurrence is rare. When it does happen, memories of the recent past are more likely to be lost than older ones. The extent of the loss varies from events that happened just some seconds back to those that occurred several years ago, depending on the strength of the learning and the severity of the disruption.

Anterograde amnesia is the inability to create new memories. The patient is trapped in an ever-present "now"--whether meeting with the same people or experiencing a recurrent event, he regards them as being new and novel, over and over again. He still has memories from before onset of the amnesia, but he cannot add to them. Common causes of this kind of memory loss include trauma, stroke, viral encephalitis, and Alzheimer's disease. All of them damage the hippocampus, which lies deep on both sides of the brain. Thiamine deficiency experienced by some chronic alcoholics also produces anterograde amnesia, by creating lesions in parts of the brain known as the mammillary bodies and the medial thalamus.

Every time we perceive something, a unique set of brain cells is activated in a specific sequence. If not pursued, the perception fades and the cells return to their original state. If the thought is entertained, the relationship between these cells is strengthened. The transmission of signals through synapses becomes easier between these cells than between cells that do not have this relationship. The set of cells with facilitated synapses is now the anatomical correlate of the memory and is called a memory engram. Once the engram is formed, anything that activates it will revive the original perception as a memory. If allowed to lie dormant for too long, this relationship dissolves and so does the memory.

Synapses between neurons that produce the neurotransmitter dopamine in the prefrontal cortex are responsible for working memory. The hippocampus of the temporal lobes is responsible for consolidating or solidifying the memory. Every time the memory engram is activated, the hippocampus facilitates the synapses and strengthens the relationship between neurons in the circuit.

Memory consolidation can occur consciously, by repetition, but it usually occurs unconsciously, by the action of the hippocampus. The latter is more likely to happen when the experience is novel, has emotional significance, or relates to something we already know. The more the engram is activated, the stronger the memory. This facilitation involves electrical, biochemical, and anatomical changes.

Most long-term memories are physically consolidated (recorded) somewhere in the 100 billion nerve cells of the brain. Initial facilitation is based on changes in the long-term electrical potentials of cells and modification of preexisting proteins. Important neurotransmitters responsible for these changes include glutamate and nitric oxide.

Stronger facilitation requires the expression (turning on) of certain genes and the synthesis of new proteins. These events produce anatomical changes in cells, including the sprouting of new branches and the creation of new synapses.

Among the substances important for this growth is a peptide called BDNF (brain-derived neurotrophic factor). New research has shown that the brain also grows new cells in response to learning. In other words, our experiences can restructure our brains.

Brain regeneration, memory genes, smart pills

Brain cell growth.For decades it has been considered a fundamental truth that adult brains never grow new cells. But one of the most exciting recent discoveries in memory research is that neurons do multiply. Recent work with monkeys has shown that new cells are constantly being made in the hippocampus, the part of the brain that consolidates long-term memories. Experts believe that this is true for human brains as well.

If we can discover how to control this intrinsic ability of the brain, we would be able to create new cells to replace dead or degenerating ones. This knowledge could lead to new treatments for stroke, trauma, or degenerative brain diseases such as Parkinson's and Alzheimer's.

Memory genes. In the 1970s, Seymour Benzer found that a particular genetic mutation in a fruit fly caused it to become a "dunce." Several years ago, Tim Tully and Jerry Yin at Cold Spring Harbor Laboratory (on Long Island in New York) developed a "smart" fruit fly by stimulating the same gene (CREB) that was mutated in Benzer's fly. CREB functions as a master switch that unlocks dozens of other genes important for the consolidation of memory. It is like a general contractor, who controls the work crews that actually do the remodeling of the synapses to create memories. Based on past experience, the CREB gene probably occurs in humans, too. But there are at least 23 other genes known to affect memory, and researchers have yet to find ways to turn on these genes selectively in the brain.

Over-the-counter drugs.Many people would like to improve their memory instantly by taking a pill. And many over-the-counter drugs and herbs- -such as choline, St. John's wort, and ginkgo biloba--are being marketed as having the ability to bolster memory. But they have not been proven to boost raw memory power.

Some of these products contain a stimulant such as caffeine. The stimulant can improve attention, and it may consequently enhance our ability to remember. Other common ingredients are antioxidants. Oxidative changes are thought to enhance the degeneration of brain cells, as seen in the brains of Alzheimer's disease (AD) patients. It has therefore been speculated that antioxidants such as vitamin E might improve the memory of AD patients and possibly that of normal elderly individuals. Studies support the idea that damage due to oxidation does play a role in AD and that antioxidants improve the independence and behavioral symptoms of AD patients. But while antioxidants may help maintain the viability of brain cells, they probably do not have any specific effect on the memory process.

Prescription drugs.Over 100 cognitive enhancers are currently being tested. Most would be used for AD patients, but some may enhance memory function in normal individuals as well. These drugs would not recover past memories that have been lost, but they would improve our ability to store new information. The tests, however, may take many years. In the case of tacrine (Cognex), the first drug approved to treat AD, it took about 15 years to go from the research lab to the doctor' s office.

One approach that is being tested is called estrogen-replacement therapy. Early evidence of estrogen's role in memory came when researchers found that the plasticity of the rat brain varied with the rat's reproductive cycle. More recently, scientists at Columbia University found that estrogen-replacement therapy was associated with a reduced risk of AD. The study involved more than a thousand women of European, Hispanic, and African ancestry. For women who did not take estrogen, the incidence rate for AD was 8.4 percent; among those who took estrogen, it was 2.7 percent. Some researchers suggest that estrogen exerts its beneficial effects by increasing the number of neuronal projections known as dendritic spines, which enhance communication between neurons. Others say that estrogen works together with compounds called neurotrophins to facilitate communication.

These and other results suggest that estrogen during and after menopause may significantly lower the risk of AD and delay the onset of memory loss. Whether it can delay memory loss due to normal aging has yet to be proven. Additional research is needed to learn the exact mechanism by which estrogen protects against memory loss, before doctors can recommend it for that purpose.

Another set of tests is being carried out with anti-inflammatory drugs. It has long been noticed that AD is less common among people with arthritis. This observation now seems related to their use of anti- inflammatory drugs. In a study by the National Institute of Aging, more than 2,000 men and women were surveyed about their use of medications. Those who regularly used nonsteroidal anti-inflammatory drugs (NSAIDs), other than aspirin, had a lower risk of developing AD than those who did not. This and other pieces of evidence suggest a relationship between brain inflammation and memory loss in cases of both AD and normal aging.

In a 3-year study of over 7,000 normal volunteers, NSAIDs were found to lower the risk of age-related loss of memory and other cognitive functions. Those taking NSAIDs showed cognitive ability equivalent to that of a person 3.5 years younger, and the risk of cognitive decline was reduced by about 20 percent. However, further testing is necessary, and the use of NSAIDs to preserve cognitive function in normal individuals is not yet advised.

In The Milk Train Doesn't Stop Here Anymore, Tennessee Williams wrote, "Life is all memory except for the one present moment that goes by you so quick you hardly catch it going." Memories are us. They are a function of our past experiences and a framework for our future selves. And what we individually choose to remember or forget is intrinsic to who we are. As demonstrated by many AD patients, without memories we are stuck in a moment in time.

Research to help prevent such tragic memory losses is praiseworthy, and efforts to enhance normal memory by improving ourselves are admirable as well. But using drugs to tinker with normal memory may not be worth it in the long run. These drugs, like most others, will take as well as give. We must think carefully about what we are giving up before we take them.

Norbert R. Myslinski is associate professor of neuroscience at the University of Maryland, past president of the Baltimore chapter of the Society for Neuroscience, and director of Maryland Brain Awareness Week.