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The Quest to Forget
Drugs to Prevent Painful Memories 

ROBIN MARANTZ HENIG / NY Times 4apr04

IN THE MAGAZINE

A 29-year-old paralegal was lying in the middle of Congress Street in downtown Boston after being run over by a bicycle messenger, and her first thought was whether her skirt was hiking up. ''Oh, why did I wear a skirt today?'' she asked herself. ''Are these people all looking at my underpants?''

Her second thought was whether she would be hit by one of the cars speeding down Congress—she wasn't aware that other pedestrians had gathered around, some of them directing traffic away from her. And her third thought was of a different trauma, eight years earlier, when driving home one night, she was sitting at a red light and found herself confronted by an armed drug addict, who forced his way into her car, made her drive to an abandoned building and tried to rape her.

''I had a feeling that this one trauma, even though it was a smaller thing, would touch off all sorts of memories about that time I was carjacked,'' said the woman, whose name is Kathleen. She worried because getting over that carjacking was something that had taken Kathleen a long time. ''For eight months at least,'' she said, ''every night before I went to bed, I'd think about it. I wouldn't be able to sleep, so I'd get up, make myself a cup of decaf tea, watch something silly on TV to get myself out of that mood. And every morning I'd wake up feeling like I had a gun against my head.''

Would Kathleen have been better off if she had been able to wipe out the memory of the attack rather than spending months seeing a psychologist and avoiding the intersection where the carjacking occurred? The answer seems straightforward: if you can ease the agony that people like Kathleen suffer by dimming the memory of their gruesome experiences, why wouldn't you? But some bioethicists would argue that Kathleen should hold on to her nightmarish memory and work through it, using common methods like psychotherapy, cognitive behavior therapy or antidepressants. Having survived the horror is part of what makes Kathleen who she is, they say, and blunting its memory would diminish her and keep her from learning from the experience, not to mention impair her ability to testify against her assailant should the chance arise.

Scientists who work with patients who suffer from post-traumatic stress disorder see the matter quite differently. As a result, they are defending and developing a new science that can be called therapeutic forgetting. True post-traumatic stress can be intractable and does not tend to respond to most therapies. So these scientists are bucking the current trend in memory research, which is to find a drug or a gene that will help people remember. They are, instead, trying to help people forget.

All of us have done things in our lives we'd rather not have done, things that flood us with remorse or pain or embarrassment whenever we call them to mind. If we could erase them from our memories, would we? Should we? Questions like these go to the nature of remembrance and have inspired films like ''Memento'' and, most recently, ''Eternal Sunshine of the Spotless Mind,'' in which two ex-lovers pay to erase their memories of each other. We are a long way from the day when scientists might be able to zap specific memories right out of our heads, like a neurological neutron bomb, but even the current research in this area ought to make us stop and think. Aren't our memories, both the good and the bad, the things that make us who we are? If we eliminate our troubling memories, or stop them from forming in the first place, are we disabling the mechanism through which people learn and grow and transform? Is a pain-free set of memories an impoverished one?

 

 

After her bike-messenger collision, Kathleen was taken to the emergency room of Massachusetts General Hospital. Once her physical wounds were attended to—she wasn't badly hurt; just a few cuts and bruises—she was approached by Anna Roglieri Healy, a psychiatric nurse. Healy was engaged in a pilot study to test whether administering drugs immediately after a traumatic event could prevent the development of post-traumatic stress disorder. Did Kathleen want to be part of the study?

''I thought it might be a good idea,'' Kathleen said recently. ''Not that I really thought I'd develop problems after this bike accident, but I knew I was prone to post-traumatic stress disorder because I developed it after my carjacking.''

Kathleen signed on to the study, which was being directed by Roger Pitman, a professor of psychiatry at Harvard Medical School. (Pitman requested that Kathleen's last name not be used for this article because of her status as a research subject.) Like the 40 other subjects, she took a blue pill four times a day for a week and a half and then gradually reduced the dosage over the course of another nine days—a total of 19 days of treatment. Half of the subjects were taking an inert placebo pill and half were taking propranolol, which interferes with the action of stress hormones in the brain.

When stress hormones like adrenaline and norepinephrine are elevated, new memories are consolidated more firmly, which is what makes the recollection of emotionally charged events so vivid, so tenacious, so strong. If these memories are especially bad, they take hold most relentlessly, and a result can be the debilitating flashbacks of post-traumatic stress disorder. Interfering with stress hormone levels by giving propranolol soon after the trauma, according to Pitman's hypothesis, could keep the destructive memories from taking hold. He doesn't expect propranolol to affect nonemotional memories, which don't depend on stress hormones for their consolidation, but he said it could possibly interfere with the consolidation of highly emotional positive memories as well as negative ones.

Pitman's hypothesis, if it is confirmed experimentally, might lead to a basic shift in our understanding of remembering and forgetting, allowing us someday to twist and change the very character of what we do and do not recall.

 

 

The idea that forgetting could ever be a good thing seems counterintuitive, especially in a culture steeped in fear of Alzheimer's disease. When it comes to memory, most people are looking for ways to have more of it, not less. If you can boost your ability to remember, you can be smarter, ace the SAT's, perform brilliantly in school and on the job, stay sharp far into old age.

But with memory, more is not always better. ''At the extreme,'' James McGaugh, director of the Center for the Neurobiology of Learning and Memory at the University of California at Irvine, said recently, ''more is worse.''

McGaugh recalled the Jorge Luis Borges short story ''Funes, the Memorious,'' in which Ireneo Funes is thrown from a horse. The injury paralyzes his body and turns his memory into a ''garbage heap.'' Funes remembers everything: ''He knew the forms of the clouds in the southern sky on the morning of April 30, 1882, and he could compare them in his memory with the veins in the marbled binding of a book he had seen only once. . . . The truth was, Funes remembered not only every leaf of every tree in every patch of forest, but every time he had perceived or imagined that leaf.''

And yet, as Borges writes, such a prodigious memory is not only not enough—it is much too much: ''[Funes] had effortlessly learned English, French, Portuguese, Latin. I suspect, nevertheless, that he was not very good at thinking. To think is to ignore (or forget) differences, to generalize, to abstract. In the teeming world of Ireneo Funes there were nothing but particulars—and they were virtually immediate particulars.''

Most of us are quite capable, sometimes far more capable than we'd like, of forgetting the particulars. Where did you park your car at the train station this morning? What's another word for pretty? What year was the Constitution ratified? So many details seem out of reach, lost in a murky mental morass. But McGaugh has found that certain memories—the ones associated with the strongest emotions—tend to stay locked in longer, sometimes for life. You can't possibly remember every time you and your wife kissed, but you probably remember the first time.

At the memory center in Irvine, McGaugh and his colleague Larry Cahill did a simple recall test that demonstrated how much more sharply people remember emotional memories than neutral ones. Cahill showed subjects a series of 12 slides and told them a story to accompany the images. The slides were always the same, but the words to the story changed from one group to another. To the first group, Cahill told an emotionally neutral story: a boy and his mother leave their home and cross the street and pass a car that has been damaged in an accident. They visit the boy's father, who works in a hospital. During their visit, the staff is having a disaster-preparation demonstration. The boy and his mother see people with makeup on to make them appear as if they have been injured. The mother makes a telephone call, goes to the bus and goes home.

To the second group, Cahill told a different story. It began the same way—a boy and his mother leave their home and cross the street—but then it diverged: the boy is hit by a car. The boy is seriously injured and is rushed to the hospital. At the hospital, surgeons work frantically to save the boy's life and to reattach his severed legs. The second story ended just the way the first one did: the mother makes a telephone call, goes to the bus and goes home.

When the subjects were taken back to the laboratory two weeks later, they were asked to describe what they had seen on the slides. Don't tell the story, they were instructed; just say what you remember about the pictures—how many people were there, what were they wearing and so on.

The people who had been told the neutral story remembered all three parts of it with the same degree of accuracy. Those who had been told the exciting story had significantly better recall of the slides corresponding to the boy's injury and operation. To McGaugh, this experiment underlines the phenomenon observed by Rene Descartes more than three centuries ago. ''The usefulness of all the passions consists in their strengthening and prolonging in the soul thoughts which are good for it to conserve,'' Descartes wrote. ''And all the harm they can do consists in their strengthening and conserving . . . others which ought not to be fixed there.''

Cahill took the experiment one step further: he gave a dose of propranolol to a new batch of subjects and showed them the same slides with the same gory story. Propranolol is one of a class of drugs known as beta blockers, usually given to heart patients to inhibit the action of adrenaline on the beta-adrenergic receptors in the heart. (Unlike some beta blockers, it acts directly on the brain.) This time, the gory story did not prove more memorable. Those receiving propranolol were able to recall the pictures no better than those who had heard the emotionally blander story. This was the first suggestion that it might be possible in humans to interfere pharmacologically with the recollection of intense memories.

McGaugh and Cahill's work gave Roger Pitman of Harvard the idea for his own study of propranolol in post-trauma treatment. It seemed to Pitman, who had spent much of his career studying post-traumatic stress in Vietnam veterans, that the drug could eventually offer relief to people disabled by horrifying, intrusive memories of battle.

''Working with veterans made it clear that post-traumatic stress disorder is different from just having bad memories,'' Pitman said. ''These men said that frequently when they remembered Vietnam, every detail came back to them—the way it smelled, the temperature, who they were with, what they heard.''

The subjects in Pitman's study had all, at one time or another, been taken to the Mass. General emergency room after a variety of traumas. Several had been sexually assaulted; one had smashed her car into a tree; another had fallen into one of the huge pits created by the Big Dig construction project that has bewildered Boston's pedestrians and drivers for more than a decade. But while Anna Healy was pleased at how many people agreed to be part of the study, not everyone in the E.R. said yes. According to Pitman, several seemed too shaken to want to relive their traumas, even under controlled experimental conditions.

While she was enrolled in Pitman's study, Kathleen said she believed she was in the placebo group, since the pills made her feel no different—no better, no worse. Three months after her accident, she went back to Mass. General and related the details of her collision, which a researcher compiled into a 100-word narrative and read into a tape recorder. A week later, Kathleen came back and listened to the tape while her physiological stress indicators (sweating, heart rate, muscle tension) were measured and compared with those of the other study subjects. When they heard the scripts of their traumas, 43 percent of the placebo group responded with increased physiological measures of stress. In the propranolol group—of which Kathleen, despite her suspicions, was part—no one did.

But when Pitman asked Kathleen and the other study subjects whether they believed that memories of their trauma were impairing their daily lives, he found no significant difference between the propranolol and the placebo groups.

The National Institute of Mental Health found these preliminary results intriguing enough to want more information about propranolol's usefulness after a trauma. The goal is nothing at all like the fictional goal in ''Eternal Sunshine of the Spotless Mind''; even if Pitman's treatment does everything he hopes, it would succeed only in easing the pain of the troubling memory, not erasing it. This summer, Pitman will begin recruiting participants for a new study financed by the institute, aiming for a total of 128. Once again he will give propranolol to half of them and a placebo pill to the other half, and he will test their physiological stress response to imagery of the trauma one and three months after it occurs.

''I'm prepared for the possibility that this second study will have negative results,'' Pitman said. ''But even if there's, say, just a 20 percent chance that I'm right, that's a 20 percent chance of finding a method that works in the secondary prevention of post-traumatic stress disorder. Think of the amount of human suffering that we would be able to avoid.''

Pitman's approach to post-traumatic stress disorder, however, is a blunt instrument. It could mean giving a drug to all the people who come to the E.R. after a trauma—at least 70 percent of whom will never develop any long-term problems even if they're left alone. The drug is a relatively safe one, with a long track record of use for hypertension, but even relatively safe drugs carry risks. (Propranolol is not used much for heart disease anymore; the beta blockers now more commonly prescribed don't tend to reach the brain and probably don't have much impact on emotional memories.) If Pitman's research leads to making propranolol standard treatment in post-trauma care, this might mean that someday people who would have recovered from their trauma quite well on their own would be given a preventive medication they didn't need.

The better approach would be to target the people prone to the disorder and to treat them immediately. The trick, of course, is knowing who they are. Studies have shown that patients with post-traumatic stress disorder tend to have a smaller than normal hippocampus—a brain region involved in memory. But is this size difference a cause of post-traumatic stress disorder or an effect? Pitman sought the answer in the brains of identical twins. He found 135 pairs of twins in which one twin had gone to Vietnam but the other had not. Some of the veterans developed post-traumatic stress disorder; others had no such problems. The noncombatant twins of the traumatized vets had smaller hippocampi than the twins of the vets who fared better psychologically. This finding suggests that a small hippocampus is a marker for susceptibility to post-traumatic stress disorder.

Another alternative to a propranolol-for-everyone approach would be to wait awhile after exposure to a trauma to see who develops debilitating symptoms. But no one is quite sure how long you can wait. When is it too late to keep these corrosive memories from taking hold? According to Barbara O. Rothbaum, director of the Trauma and Anxiety Recovery Program at Emory University, it takes at least a couple of weeks to see who will encounter long-term psychiatric problems after trauma.

''In general, the initial response is not predictive of who is going to have a chronic disorder,'' she said. Immediate problems, according to Rothbaum, are almost inevitable: nightmares, difficulty sleeping, obsessive thoughts about the trauma.

''Most people come down a lot after the first month,'' she said. ''After that, the people who are going to improve continue to improve.'' And the ones who don't improve stay stuck. The rule of thumb, Rothbaum said, is that people with symptoms after four months will probably still have symptoms after four years—and if left untreated, some of those symptoms may persist not just for years but for decades. The problem is that if you wait until you know who really needs treatment, you may lose the chance to make that treatment effective.

One way out of this dilemma may be through the window opened by memory reconsolidation. Memories, even intense and troubling memories, seem to be vulnerable to erasure at many points during a person's lifetime. This means that it could work to hold off on propranolol or other drug therapy until recurring problems develop.

''When you retrieve a memory, that's a time when you update it with all the relevant things that happened since you stored it,'' said Joseph LeDoux, the Henry and Lucy Moses Professor of Neuroscience at New York University. When a traumatic memory is brought forth, he said—the scripted imagery used in Pitman's experiment is one way to accomplish this—it is in a fragile state. And research suggests that unless it is reconsolidated with the formation of new proteins in the brain, the memory starts to disappear.

LeDoux and his colleague Karim Nader have studied the mechanism of memory reconsolidation in laboratory rats. He trained the rats to be afraid of a musical tone by following the tone with a mild electrical shock to the foot. Twenty-four hours later, he played the tone once more, thus reactivating the traumatic ''fear memory'' in the rats. But instead of giving a shock, he delivered a dose of anisomycin directly into the rats' brains. Anisomycin, a compound approved only for use in experimental animals, inhibits the synthesis of protein, which is needed to form the new synapses that are part of both memory consolidation and reconsolidation.

For about two hours the fear memory persisted: the rats heard the tone, and they froze in fear. But 24 hours later, playing the tone elicited no such fear response. ''It was as though the fear memory had totally disappeared,'' LeDoux said. Anisomycin had prevented the synthesis of protein—and without new protein, the reconsolidated memory could not be glued into place, and the original memory apparently vanished.

What LeDoux doesn't know is whether the original memory is lost or simply can't be retrieved. ''We have trouble determining whether the failure to show the fear memory is because you've blocked encoding of the memory itself or of its retrieval,'' he said. ''Maybe the memory is still in the brain, but the animal just can't get at it.'' The distinction is relevant because memories that appeared to be lost sometimes have a habit of re-emerging.

Pitman points to rat research suggesting that the original memory is indeed still there, deep inside the brain, even if the animal's behavior makes it look as if it is lost. In one intriguing extension of LeDoux's experiment, the rats looked perfectly serene when the original fear-inducing musical tone was played: no frightened freezes. However, their amygdala, the region of the brain activated by fear, had not forgotten to be afraid; it remained just as ready to generate a fear response. What seemed to be happening was that another region of the brain, the infralimbic cortex, was signaling that fear was no longer necessary. The infralimbic cortex was keeping the amygdala from generating the fear response—but the fear was still there, blocked and buried.

According to Pitman, this finding indicates that long-dormant fears can reawaken and might explain why Kathleen's relatively minor dust-up with the bike messenger set off memories of her earlier, deeper terror after the carjacking and sexual assault. Or it could explain why a World War II veteran, who had recovered from post-traumatic stress disorder decades earlier, gets a diagnosis of prostate cancer in his 60's and begins having nightmares about battlefield horrors that took place 40 years before.

 

 

If memories of a horrific trauma are haunting someone, overwhelming him with fresh, immobilizing feelings whenever he remembers the original event, should he be forced to hold onto those memories? Some would answer yes. Late last year, the President's Council on Bioethics issued a report called ''Beyond Therapy: Biotechnology and the Pursuit of Happiness,'' which dealt in part with the possibility of therapeutic forgetting. It concluded that it was not necessarily wise.

''Changing the content of our memories or altering their emotional tonalities, however desirable to alleviate guilty or painful consciousness, could subtly reshape who we are,'' the council wrote in ''Beyond Therapy.'' ''Distress, anxiety and sorrow [are] appropriate reflections of the fragility of human life.'' If scientists found a drug that could dissociate our personal histories from our recollections of our histories, this could ''jeopardize . . . our ability to confront, responsibly and with dignity, the imperfections and limits of our lives and those of others.''

One council member, Rebecca Dresser, expressed the majority sentiment during a council session in late 2002. The ability to suffer the ''sting'' of a painful memory is ''where a lot of empathy comes from,'' said Dresser, a professor of ethics in medicine at Washington University in St. Louis. ''That is, when we have an embarrassing experience, we develop empathy for others who have a similar experience. . . . We want some of that sting. So the question is: what is dysfunctional sting?''

The difficulty is defining ''dysfunctional,'' since the sting that's dysfunctional for an individual is different from the sting that's dysfunctional for society. As Dresser pointed out, society has a stake in having its citizens retain their own painful, awkward memories as a check on behavior. ''There probably is some sting that we would rather not have as individuals,'' she said, ''but it's good for the rest of us that others have it.''

Some ethicists add that it's also good for the people who are suffering themselves; the painful memories, they say, are all part of what makes us who we are, and diminishing them would diminish our humanity.

''Would dulling our memory of terrible things make us too comfortable with the world, unmoved by suffering, wrongdoing or cruelty?'' asks the bioethics council in its report. ''Does not the experience of hard truths—of the unchosen, the inexplicable, the tragic—remind us that we can never be fully at home in the world, especially if we are to take seriously the reality of human evil?'' The council also asked whether the blunting of our recollections of ''shameful, fearful and hateful things'' might also blunt our memories of the most wondrous parts of our lives. ''Can we become numb to life's sharpest arrows without becoming numb to its greatest joys?''

Still, to scientists who study memory, there is nothing beneficial, for either individuals or for society, about debilitating, unbidden memories of combat, rape or acts of terrorism. ''Going through difficult experiences is what life is all about; it's not all honey and roses,'' said Eric Kandel, a professor of psychiatry and physiology at Columbia University. ''But some experiences are different. When society asks a soldier to go through battle to protect our country, for instance, then society has a responsibility to help that soldier get through the aftermath of having seen the horrors of war.''

Of course, post-battlefield remorse serves as a check on our militaristic tendencies. Vietnam veterans haunted by memories of combat were among the most forceful opponents of the war after their return home. But have we the right to buy a surrogate conscience at the cost of thousands of ruined lives? If we have the responsibility to treat veterans' physical wounds, don't we also have a responsibility to ease their psychic suffering?

The human condition remains rich and complicated even without that psychic pain, said William May, an emeritus professor of ethics at Southern Methodist University in Dallas and a former member of the President's Council on Bioethics. ''Perhaps just as dangerous as writing out memory,'' May said at the same council session at which Dresser spoke, ''is the reliving of a past event that is so wincing in memory that one engages in a kind of suffering all over again, which is unproductive of a future.'' Remorse can be ''unavailing,'' he said, and can leave a person stuck ceaselessly in the past.

Without witnessing the torment of unremitting post-traumatic stress disorder, it is easy to exaggerate the benefits of holding on to bitter memories. But a person crippled by memories is a diminished person; there is nothing ennobling about it. If we as a society decide it's better to keep people locked in their anguish because of some idealized view of what it means to be human, we might be revealing ourselves to be a society with a twisted notion of what being human really means.

Robin Marantz Henig is the author of ''Pandora's Baby: How the First Test Tube Babies Sparked the Reproductive Revolution.''

source: http://query.nytimes.com/mem/tnt.html?tntget=2004/04/04/college/coll04MEMORY.html&tntemail0=&pagewanted=print&position= 4apr04

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