For patient ”J,” it was like being transported 40 years into the future. When he awoke in the hospital, he thought that he was 14 years old, that he had just played baseball with his teenaged friends and that he had been struck on the head with a bat.
A woman who looked older than his mother was standing at his bedside.
She said she was his wife, that he had children, a job and that he was 53 years old.
Unbelieving, he walked to a mirror, expecting to see his adolescent face. Instead he was shocked to see a stranger staring back. The reflection in the mirror was of an unfamiliar, lined face.
Patient ”J” has never recovered the four lost decades of his memory between the time he was hit on the head with a baseball bat and when he was found unconscious on his kitchen floor in a small Midwestern town. But he can remember things since he woke up in 1984, according to his doctors at Johns Hopkins University Medical Center in Baltimore.
He still thinks and feels like a teenager: He plays on escalators, giggles when he`s amused, has had to relearn how to shave and complains that he has ”no one to play with.”
One of the last things he remembers is traveling through Chicago and reading an account in The Tribune about the B-25 bomber that crashed into the Empire State Building on July 28, 1945. He doesn`t remember that the atomic bomb was dropped on Hiroshima nine days later.
This unusual case of retrograde amnesia is fascinating to scientists. It is one of nature`s experiments that may provide insights into mankind`s greatest possession, the ability to learn and remember.
It is also frightening because it shows that if you take away someone`s memory, you take away everything the person is. For victims of Alzheimer`s disease and other disorders, the loss of memory is in effect the loss of humanity.
Yet a revolution in brain research is providing scientists the means to explore not only restoration of memory but also new ways to enhance it. What makes a person unique and determines his special talents is his ability to acquire new knowledge and to store it. There is no thought without memory.
”That`s what makes us the most advanced creatures on Earth,” said Dr. Daniel Alkon, codirector of the laboratory of cellular and molecular biology of the National Institute of Neurological and Communicative Disorders and Stroke, Bethesda, Md.
”We take in patterns of stimulation from our environment,” he explained, and through this process learn the cause-and-effect relationships that enable us to learn from experience and predict the outcome of events.
The human brain, unlike the brain of any other animal, has the ability to associate anything it senses from its environment with any memory it has already stored. Out of that ability come new concepts, new ideas and ultimately imagination. It`s what forms and changes our behavior.
Animals also have memory, but, as far as scientists know, it is basically limited to making direct associations, such as between a stimulus and a response. An animal`s memory can associate things from A to B but not from A to Z. A dog, for example, will anticipate receiving food from its owner each day. But a human can anticipate the need for food next year and plant crops to meet those needs.
”The human species, unlike the monkey, is made to build civilizations, and building civilizations means you have to acquire information,” said Dr. Marek-Marsel Mesulam, a Harvard University behavioral neurologist.
Learning in humans has become so effective that it has created a new type of evolution-cultural evolution, said Eric Kandel of Columbia University. In effect, it means not having to reinvent the wheel with each generation.
”Cultural evolution supports the purposes of biologic evolution in sustaining, in a nongenetic way, a means of transmitting knowledge from generation to generation,” he wrote.
Hopkins scientists don`t know whether patient ”J`s” memory has been wiped out or whether access to it has been blocked by some psychological phenomenon. His problem became known after he was found on the kitchen floor clutching an oven heating element that he apparently had been trying to replace.
Whether it was an electric shock or something else that triggered his loss of memory, no one knows. All he said at the time was that he was 14, it was early August, 1945, and he was in his hometown. If it was an electric shock, it might have wiped out all memory that had been formed since he was hit on the head with a bat, like an electrical surge that wipes out a computer memory disk, said Neal J. Cohen, a Hopkins neuropsychologist.
But his case dramatically shows how nearly a lifetime of information, knowledge and skills can vanish, turning a 53-year-old man into a boy.
”In `J`s` case the difference is enormous,” Cohen said. ”Suddenly he`s sort of a prepubescent 14-year-old. That`s a radical change in how he approaches the world.”
Beyond restoration and enhancement of memory, understanding how the brain stores and retrieves information could lead to construction of machines that can learn and think.
”What we are limited by are the things we can`t sense, like invisible wavelengths,” Alkon said. ”If we can extend what we can sense with artificial machines, we can extend our associative capacity. Theoretically, we can build machines that can learn even better than we do. Maybe they will give us a better insight about our universe.”
The brain is both old-fashioned and ultramodern. It is old-fashioned because it has been evolving for more than 2 million years. ”For the investigator it is not a very user-friendly organ,” Mesulam said. ”If I were putting the brain together, this is not the way I would do it. It`s very hard to service, and it`s not a very logical piece of equipment.”
Like everything else in evolution, the brain was put together by trial and error, he explained. Nature tries something, and if it works, it gets added on, he said. After millions of years, there is a confusing
conglomeration of parts because they weren`t assembled in an orderly, sequential fashion, he said.
Nevertheless, the brain is modern because it has evolved to the point where adjusting to change is what it likes to do. It has become an organ for all ages, he said, and is unlikely to restructure its components drastically over the next 2 million years.
”The brain is here to stay, whether you like it or not,” Mesulam said.
”Its greatest feature is its adaptability, which is good and bad. It`s good, of course, because you adapt. It`s bad because it can tolerate a lot of things that are very bad.
”The human brain is so flexible that it can even adapt itself to atrocities, to terrible things, and it stops being shocked or doing anything about them.” For instance, wars, famine, poverty and disease become part of our nightly newscasts, and they come to be accepted as routine, he explained. Prying loose the secrets of memory will be difficult, but scientists are busy tracking down the chemical and physical changes that occur in the brain when memory is laid down.
One of the biggest puzzles is why everything you see or sense isn`t recorded in memory. The brain is selective about what it stores, and perhaps 99.9 percent of the information that the brain processes is consigned to oblivion.
The secret to what is retained may lie in hormones and the emotions they regulate, at least for some important types of memory. The first time you encounter a predator, a wild dog, for instance, you won`t know whether it`s dangerous until it tries to attack you. When it attacks, the level of your fight-or-flight hormone-adrenalin-shoots up and you run away. A vivid memory of the predator has been laid down, and the next time it is encountered there is no question about the danger it poses.
Hormones, which have been found to act as neurotransmitters, or chemical messengers in the brain, are associated with other emotionally charged behavior, such as sex, eating and anything else important to survival.
When a specific hormone level rises sharply, it is basically telling the brain that it should pay attention because something important has to be learned, said Dr. Robert Rose, a University of Chicago psychiatrist. If hormone levels remain low, they are telling the brain that an event is mundane or inconsequential and does not have to be deposited in memory, he explained. ”Almost everything that has a survival value has its own specific set of hormonal consequences,” Rose said. ”The hormonal consequences of a given event may play a good part of the role in deciding whether that event should be laid down as memory or not.”
The things that are most vividly remembered tend to be emotion-laden, such as getting married, having a baby, a first love, an accident, winning a contest or President John Kennedy`s assassination.
By injecting one of these hormones, a compound called ACTH
(adrenocorticotropic hormone), into volunteers, Rose has been able to improve their memories in preliminary studies.
ACTH is a stress hormone. It increases in the body at the first sign of stress, whether psychological, such as facing an irate boss, or physical, such as being pinched.
Basically ACTH tells the brain to pay attention, Rose said. When the hormone was injected into volunteers it appeared to raise their attention levels so they could learn tasks better than subjects given placebos, he said. Impaired memory is one symptom of depression, and that may be linked to abnormally low levels of certain hormones in these patients, he said.
Rose plans to start human trials with other hormones that have succeeded in improving learning and memory in animals, such as vasopression, corticoid steroid and endorphins.
”There`s incredible activity in the pharmaceutical industry these days in looking for memory-enhancing drugs,” he said. ”If you could come up with something that was benign and that would help somebody`s everyday memory, everybody would be popping it.”
Endorphins and enkephalins, which have been called the brain`s own opiates, may serve as a reward for learning, said Dr. Solomon Snyder, chief of neuroscience at Hopkins. Both were discovered after scientists became curious about why some brain cells would have specific areas called receptors where morphine and other opiates attach. Once attached, they transmit their chemical message to the cell. Scientists assume that the brain`s natural opiates, which lock onto these same receptors, are involved in relieving pain and making people feel good.
”It`s quite possible that endorphins and enkephalins (natural opiates)
would be involved in the reward mechanism that enables us to learn,” said Snyder, one of the pioneering discoverers of the opiate receptors. ”One crucial part of learning is the reward mechanism. Something`s got to make you feel good for having learned something new or else you won`t learn.”
Just as the brain can learn the right thing to do, it can learn the wrong thing. Abnormal learning, researchers are beginning to find, may play a key role in triggering or exacerbating mental problems.
Scientists at the National Institute of Mental Health have found that cocaine can mimic the effects of stress hormones but in a way that tosses a deadly monkey wrench into the learning and memory process.
Tests in a variety of animals show that small doses of cocaine administered to their brains at first cause no response. But the same dosage repeatedly given produces an increasingly severe response, eventually provoking seizures. Scientists call it ”kindling” because it`s like an ember that suddenly flares up into a blaze.
”Kindling is a learning mechanism,” said Dr. Robert M. Post, chief of the National Institute of Mental Health`s biological psychiatry branch. ”The brain is not getting damaged. What is happening is that the brain is learning to react more to the same stimulation over time.”
Eventually the brain reaches a point where it becomes overloaded, triggering a seizure, similar to a short-circuit in an electrical system.
”This can explain why a number of people have actually died of cocaine-related seizures,” he said.
Kindling is a model for how learning and memory mechanisms in the brain can go increasingly awry in response to the same stimulation. It may even explain how stress can worsen some mental disorders by making episodes occur more frequently.
Carbamazepine, a drug that blocks kindling, appears to prevent manic and depressive episodes from becoming more frequent and more severe, Post said. Other studies have noted similar findings. Early treatment of major mental disorders can often prevent them from becoming worse.
Post and his colleagues are exploring the hypothesis that kindling can cause some serious disorders, such as turning a few relatively harmless incidents of depression into a chronic problem. Depression may be caused by some stressful event. But if kindling takes over, the depression may begin to occur spontaneously without being triggerd by a stressful event.
Researchers divide memory into four types. Fleeting memory is like a wisp. It comes and goes almost instanenously. Immediate memory lasts for a few moments, the kind that allows you to repeat a series of numbers and then not remember them the next minute. Short-term memory may last for hours, and long- term memory may last a lifetime.
Employing imaging and other techniques, Mortimer Mishkin of the Institute of Mental Health has been tracking the circuits in the brains of animals from the point where information comes in to where it finally ends up. The work has been arduous because information takes only milliseconds to pass from one stage to another.
His work supports the theorized importance of emotions and the hormones that accompany them in laying down memory, but he finds that repetition can produce the same effect, except that it takes much longer.
”We`re trying to understand the way in which information flows through the brain,” Mishkin said. ”You can almost see it doing that now with the imaging techniques and the electrophysiological experiments.”
The trip is fantastic. Information coming in from the eye, for example, goes to the visual cortex at the back of the brain, where specialized neurons or brain cells recognize particular parts of the coded signal. From there it is shunted to the limbic system deep in the center of the brain, which governs emotions.
The information whirls around the limbic system, especially the hippocampus and the amygdala, two key structures involved in emotions and memory, and is bounced back to parts of the cortex, including the region from which it came. The information then goes back to the limbic system. Mishkin has shown that with the removal of both the amygdala and hippocampus, which are rich hormone sources, memory does not get laid down.
All this time, which is only a fraction of a second, the information exists as a trace. Finally the limbic system decides either to keep the information or let it disappear.
If the decision is to keep it, the information is passed to the neurotransmitter system, which reaches out to billons of neurons all over the brain. They send out their hormonelike transmitters, such as noradrenalin, serotonin and acetylcholine, to trap the fleeting message.
When the message comes up from the neurotransmitter system to the cortex, through which the information has been passing, and is still leaving very short-lasting traces, it`s like pushing the ”print” button on a computer to print the message, Mishkin said. ”If there is no print, the message is forgotten.”
Getting the brain to artificially print these messages is the goal of Dr. James McGaugh, director of the Center for the Neurobiology of Learning and Memory at the University of California, Irvine. Giving rats small doses of adrenalin shortly after a learning task improves their memory of the task for more than a month. McGaugh recently received an $860,000 grant from the National Institute of Mental Health to study the effect of hormones and drugs on memory.
Other scientists are investigating how ”print” is translated into the various chemical and structural changes of neurons that account for the different types of memory.
Working with Aplysia, a sea snail that has only 20,000 neurons, Eric Kandel of Columbia University and his colleagues have shown that synaptic connections, the points on cell surfaces where neurons talk to each other, are modified by learning in such a way that information has an easier or harder time getting through.
Exposing the snail to a potentially dangerous stimulus causes synapses to become more powerful. They are on full alert and are ready to respond quickly to the slightest hint of danger.
These same synapses, on the other hand, become weaker and may even disconnect during habituation. Habituation occurs after the snail has learned a response to a new stimulus but then decides it can ignore the stimulus because it is trivial.
”In all the forms of learning that have been looked at, a critical feature seems to be an alteration in the strength of connections between cells,” Kandel said.
At the same time there is a growing body of information suggesting that learning stimulates the growth of new connecting fibers between nerve cells that seem to serve as storage units for memory.
William T. Greenough, a University of Illinois neuropsychologist, has shown that new connections may form in a matter of minutes after a learning experience.
”What was really surprising about it was not necessarily that there would be new synapses,” he said, ”but that they would form in minutes was just something that people did not expect.”
Preliminary evidence that may help explain another difference between short- and long-term memory has been found by Kandel`s group. Short-term memory seems to involve certain natural chemical compounds called proteins that already exist in neurons. Like all other cells in the body, neurons produce a wide variety of proteins to carry on their normal operations. Long- term memory may require turning on slumbering genes. The genes then direct the production of new proteins needed to give a permanent berth to a memory trace.
Some of these proteins may play a role in changing the cell`s excitability. Alkon, of the National Institute of Neurological and
Communicative Disorders and Stroke, found in studies with Hermissenda, another sea snail, that learning causes potassium channels in brain-cell membranes to shrink or close down.
As a result, less potassium can leave the cell and so it builds up inside, causing the cell to develop a stronger positive charge of electricity. The flow of potassium and other positively or negatively charged ions through membrane channels is what allows a neuron to fire an electrical charge in response to incoming information.
”Now, in response to an input, that cell is going to give a larger signal,” Alkon said. ”You`re essentially transforming the way the information is flowing, and this transformation accounts for the learned relationship between the stimulus and the response.”
Despite these exciting advances in molecular biology, scientists have a long way to go in explaining how the pieces they are studying work together to produce the amazing function of the brain. To some it seems that the brain is greater than its parts. To others it is a natural consequence of biological systems that become increasingly complex.
It also touches on the question of determinism versus free will.
”I believe that we have programs for a potential to learn,” Alkon said. ”What our nervous system is wired up to do genetically defines a range of possibilities. It doesn`t tell you which possibility you`re going to learn. It just defines a universe of possibilities.
”What`s not programmed are the relationships we learn,” he said. ”That comes from the experiences we encounter. So the experience meets the genetic program, and it`s that interaction that redefines the way information flows in the brain.”
But for patient ”J” that process inexplicably became tragically short-circuited. He thinks that somehow he stumbled into a different world, like a character in ”The Twilight Zone,” a TV show he frequently watches. He keeps hoping that something will come along to transport him back.
MAPPING THE LEARNING AND MEMORY PATHWAYS OF THE BRAIN
The dramatic image to the right (and in color on page 1) is a map of the learning and memory pathways of the brain. It is called a PET (positron emission tomography) scan and provides new information about how the brain processes information.
Until recently scientists thought that when you heard or saw a word, the information was transformed into the same code and processed along a common pathway. This method of handling information was called ”serial processing.” But it is clear from the PET images that the brain processes language information along different pathways, which is called ”parallel processing,” said Peter Fox, a neuroscientist at Washington University in St. Louis, where pioneering brain-imaging studies are being conducted. Parallel processing allows the brain to do more things at once and to do them faster, he said. It is what allows you to listen to a telephone conversation and read a newspaper at the same time, he explained.
”For the first time we are able to study the organization of the cortex
(the area of the brain responsible for higher learning) on many fronts,”
Fox said.
The hot spots in the images are produced by a form of radioactive oxygen known as Oxygen 15.
Harmless doses of the radioactive material are injected into volunteers;
brain cells increase their consumption of the radioactive oxygen as their activity increases, thereby enabling scientists to trace the mental activity taking place in the brain when different functions are being performed.
The PET scan measures the location and amount of radioactive oxygen present in the brain. The hottest color, red, represents the highest level of brain-cell activity; next comes yellow, then green and blue, indicating decreasing levels of activity.
The four images represent the different areas of the brain involved in hearing, seeing, speaking and thinking words. The words given to the volunteers were common nouns, such as ”chair,” ”house,” ”car” and
”telephone.”
The resulting images depict four different brain processes:
Hearing a word: There are two main active spots on this image. The front spot is the area that processes sounds. It lights up whenever you hear any kind of sound, such as a bell, whistle or slamming door, including the sound of a word. It appears on both the right and left sides of the brain. The second spot, behind the first one, differentiates words from other sounds. It lights up only when you hear words, and it appears only on the left side of the brain, which controls language.
Seeing a word: The bright spot at the back of the brain, in the area called the visual cortex, lights up at whatever you see, be it a flash of light or a tree. The spot in front of it lights up only when you see words, and it appears on both sides of the brain.
Speaking a word: Two spots are in the center of the brain image. The top one is the area of the brain that controls the muscles of the mouth. The bottom one is an area that regulates complicated movements involved with speech.
Thinking a word: The hot spot is at the front of the brain. Called the frontal cortex, this part of the brain is involved in the highest levels of intelligence and lights up when volunteers think about the meaning of a word. For example, volunteers were told a noun and asked to think of an appropriate verb. If they were told ”chair,” an appropriate response would be ”sit.”
