AND REMEMBERING: Learning to Forget
By Greg Miller
April 02, 2004
runs amok, past pain can disrupt someone's present. New
drugs, psychotherapeutic approaches, and other strategies
might temper traumatic memories
Memory lends our lives a sense of continuity,
enabling us to learn from experience, nurture lasting
relationships, and keep good times from vanishing into
the past. But memory also brings pain. A humiliating failure,
a gruesome accident scene, or the death of a parent can
torment the mind long after the event. In extreme cases,
bad memories unravel lives, as they do for people with
posttraumatic stress disorder (PTSD) and other anxiety
conditions. Remembering the good times is nice, but forgetting
the really awful times--or at least keeping those memories
in check--may matter more for quality of life.
After decades of intense and fruitful research
on how the brain encodes new memories, many neurobiologists
are now turning their attention to how the brain keeps
unwanted memories at bay. Recent work has identified key
brain regions involved in suppressing memories and fingered
some of the chemical messengers involved. Applying their
work to the clinic, some researchers have seen promising
preliminary results with drugs that either weaken the
emotional hold of traumatic memories or prevent newly
formed memories from becoming destructive in the first
place. These studies may open the way to treatments that
return normalcy to the lives of millions of people hamstrung
by anxiety disorders.
But this work makes some bioethicists--including
those on President George W. Bush's Council on Bioethics
--squirm. They foresee a not-so-brave new world in which
the cares and fears of everyday
life can be erased by tossing back a pill--much to society's
Persistence of memory
Memories of traumatic events tend to endure, says Roger
Pitman, a psychiatrist at Harvard Medical School in Boston,
because "evolution has found a way to make us remember
things that are important for our survival." A caveman
who encounters a vicious animal while taking a shortcut
to the water hole will likely remember the experience
and avoid that route in the future.
Circuits in the amygdala and other brain
regions specialize in cementing associations like the
one between the shortcut and the animal, which are bolstered
by hormones pumped out in times of stress. "The same
adrenaline that's making you run from the animal is working
in your brain to strengthen associations between the route
and the animal," says Pitman.
But traumatic memories that are too powerful
can be detrimental. If the caveman lies awake night after
night reliving the attack, he may lose his effectiveness
as a hunter.
Nearly a century ago, Sigmund Freud proposed
that repression--"turning something away and keeping
it at a distance from the conscious"--is a basic
psychological defense mechanism. The authors of a recent
brain- imaging study claim to have found something like
what Freud described (Science, 9 January, p.
They identified a network of brain regions that keeps
unwanted memories below the surface of consciousness.
Michael Anderson of the University of Oregon
in Eugene and colleagues at Stanford University used functional
magnetic resonance imaging (fMRI) to monitor the brain
activity of volunteers trained to suppress memories--not
bad ones in this case, but bland associations. Volunteers
memorized pairs of words, such as "ordeal" and
"roach." Then, inside the scanner, single words
flashed on a screen in either green or red letters. If
"ordeal" appeared in green, subjects were instructed
to recall "roach." But if "ordeal"
was written in red, they were to avoid thinking "roach."
Distress control. When
subjects "reappraise" a disturbing image such
as a blood-spattered toilet with a less disconcerting
explanation, their amygdala activity is similar to that
evoked by a neutral image such as a file cabinet.
On a paper-and-pencil test taken after the
scanning session, subjects were about 10% worse at remembering
word pairs they'd suppressed compared to ones they'd recalled.
The brain scans hint at why. When subjects suppressed
a memory, their dorsolateral prefrontal cortex was active.
This area has been linked frequently to what cognitive
neuroscientists call executive control; it is active,
for example, when subjects consciously suppress a particular
movement or emotion. At the same time, activity in the
hippocampus--a key memory center--decreased. "What
this shows is that when people are trying to suppress
a memory, they're doing something very active that involves
a distinct network of [brain] regions," Anderson
"It's a very interesting paper on a really underexplored
topic," says Elizabeth Phelps, a cognitive neuroscientist
at New York University. "How we forget, or inhibit,
or do away with a memory [has] always been a big part
of the story, but it's one we haven't really focused on."
Anderson plans to repeat the experiment
in people who have trouble forgetting, such as those with
PTSD. "We might find that people with PTSD are deficient
in their ability to recruit this network," he hypothesizes.
There are at least two lines of defense
when faced with a traumatic experience, says Kevin Ochsner,
now at Columbia University in New York City, who collaborated
with Anderson on the Science study: Don't remember it
happened, or given that it happened, reinterpret it in
a more positive light. Just as the dorsolateral prefrontal
cortex may dampen activity in the hippocampus to manage
memory, it may play an analogous role in managing emotions.
It dampens activity in the amygdala when people try to
put a positive spin on a bad situation, Ochsner claims.
He and colleagues showed volunteers a set
of disturbing photos--a burned body, a gunshot wound,
a toilet spattered with blood or vomit--and asked them
to concoct a story in their mind that made the situation
less negative. In fMRI scans, the prefrontal cortex lit
up when subjects "reappraised," and the amygdala
grew quieter. In fact, subjects' amygdala activity during
reappraisal of negative images was similar to that during
passive viewing of neutral images such as a file cabinet.
Both Anderson and Ochsner see their findings
as illustrating everyday cognitive processes. "There's
this spin control we're doing all the time," says
Ochsner, whether we're dealing with a bad review on a
journal article or rehashing an argument with a friend.
But the work may shed light on psychiatric disorders as
"We know a lot about the pathophysiology"
of depression, Ochsner says, "but we don't know what
the pathophysiology reveals." For example, some studies
have found heightened amygdala activity and decreased
prefrontal cortex activity in depressed people. That might
mean people with depression are less able to tap into
the neural networks for reappraisal, Ochsner speculates.
Stimulating sluggish frontal regions, perhaps
with drugs or transcranial magnetic stimulation (TMS)
(Science, 18 May 2001, p. 1284),
might improve people's ability to place painful memories
in context. A study published in the March issue of the
American Journal of Psychiatry found that 10 daily sessions
of TMS focused on the right dorsolateral prefrontal cortex
had a therapeutic effect on 10 PTSD patients.
Clinical payoffs might also come from research on the
signaling molecules involved in learning--and unlearning--fear.
Much of this work involves a behavioral training regime
called fear conditioning. Typically, researchers present
a lab rat with a flash of light followed by a mild shock.
After a few repetitions, the rat exhibits a "fear
response," freezing when it sees a flash. If researchers
cease pairing each flash with a shock, the rat eventually
stops freezing--a process called extinction.
Although extinction may seem like a simple
matter of forgetting, it is not. In a rat that has seemingly
lost its fear of light flashes
through extinction, the fear response comes back with
a vengeance when the light is once again followed by a
shock. Many researchers see in extinction a parallel to
psychiatric therapy: Both involve a special kind of learning
that is prone to relapse.
Drugs that hasten or fortify extinction,
some researchers reason, might be useful for therapies
that help people overcome fearful
associations. One compound, D-cycloserine, has already
shown promise in a clinical trial. The drug enhances the
function of a particular receptor for the neurotransmitter
glutamate--the so-called NMDA receptor--that earlier work
has shown to be critical for extinction. Michael Davis
and colleagues at Emory University in Atlanta, Georgia,
found that administering the drug to acrophobic patients
during therapy--playing a virtual reality game that simulates
riding a glass elevator --helps ease their fear
of heights in real life (Science, 21 November
2003, p. 1321).
Other groups have identified additional
candidate extinction promoters. Mark Barad, a psychiatrist
at the University of California (UC), Los Angeles, says
his team is organizing a clinical trial of yohimbine,
a drug that stimulates activity of the neurotransmitter
norepinephrine and provides an "enormous boost"
to extinction in rats. Cannabinoids--the psychoactive
ingredients in marijuana--may also have potential. In
2002, Beat Lutz and colleagues at the Max Planck Institute
of Psychiatry in Munich, Germany, reported in Nature Neuroscience
that mice lacking cannabinoid receptors are impaired in
extinction but not other types of learning. Since then
his group has been screening cannabinoids and related
compounds for ones that aid extinction. The list of candidates
also includes drugs that enhance the activity of certain
calcium channels or the inhibitory neurotransmitter GABA.
Researchers have yet to form a clear picture of how all
these signaling molecules fit together.
M. C. ANDERSON ET AL., SCIENCE 303, 234
Suppress that thought.
Activity in the dorsolateral prefrontal cortex (arrows)
puts a damper on unwanted memories.
It may also be possible to make extinction
--and potentially therapy--more effective without drugs.
Barad's group reported in the Journal of Experimental
Psychology: Animal Behavior Processes last October that
the timing of extinction training has a big influence
on its effectiveness. Rats get over their trained fear
of light flashes more quickly when exposure to the flash
alone is delivered in clusters than when the flashes are
evenly spread out.
Subsequent experiments hint that continuous exposure to
the feared stimulus is even better than clusters, Barad
says. He sees parallels in his psychiatric practice. One
patient with obsessive-compulsive disorder had an irrational
fear of catching cancer from people who have cancer, including
her mother. Barad convinced her to wear a scarf that belonged
to her mother continuously, and over time her fear disappeared.
"We learn fear very easily," Barad
says, and extinction is the brain's way of weeding out
maladaptive associations. Tapping into this natural learning
process--whether through drugs or therapy or both--could
help patients with a variety of disorders conquer bad
associations. Extinction experiments can teach therapists
how to expose people more effectively to feared cues and
prevent them from expressing inappropriate behaviors in
response, Barad says.
It never happened
While some researchers work on aids to unlearning, another
set of recent studies suggests that it may be possible
to prevent newly formed memories of traumatic events from
becoming disruptive. Techniques could weaken both the
memories themselves and their emotional associations.
Memories of emotionally significant events
are strengthened by stress hormones such as adrenaline.
A classic study by Larry Cahill and James McGaugh of UC
Irvine published a decade ago showed that blunting the
effects of stress hormones in the brain can negate this
strengthening effect. Volunteers viewed a slide show and
listened to a narrative about the slides--either a tame
one about a boy visiting his father at work or a tragic
version of the same story. A week later, subjects remembered
the emotional story much better. But subjects who received
propranolol--a beta-blocker drug, named for the subtype
of adrenergic receptor it blocks--remembered the emotional
story no better than the neutral one. Propranolol blocks
the effects of the neurotransmitter norepinephrine, levels
of which rise in the brain in response to adrenaline.
The researchers concluded that adrenergic activity--brain
signals transmitted by members of the adrenaline family--is
essential for the enhancement of emotional memories.
Problematic. The President's
Council on Bioethics warns against manipulating memories.
Subsequent research has hinted that adrenergic
activation plays a role in the development of PTSD. People
who show greater signs of adrenergic activation, such
as a racing heart rate and panicky behavior, immediately
after a traumatic event are more likely to exhibit symptoms
of PTSD later, says Charles Marmar, a psychiatrist at
UC San Francisco.
Together with colleagues in France, Marmar
recently gave propranolol to 11 people admitted to French
hospitals following a motor vehicle accident or physical
assault. The patients, who did not have serious physical
injuries, took the drug within a few hours of the incident
in most cases and continued to take it for 2 to 3 weeks.
Two months later, this group had fewer symptoms of posttraumatic
stress than a similar group of patients that didn't take
the drug. A previous pilot study by Pitman and colleagues,
published in 2002, found similar results.
Both Pitman and Marmar say the findings
are encouraging but preliminary. "You can't take
this to the bank," Marmar says of the combined results,
"but I think it's enough to justify a large-scale
trial." Indeed, both groups learned late last year
that they will receive funding for larger, blinded, placebo-controlled
trials. "If this is all correct, it means that PTSD,
which affects close to 8% of the American population at
some point in their life, might be predictable at the
time of the event and may even be preventable ... with
a course of medication that costs $15," Marmar says.
Medicating away morality?
But that doesn't sound like a bargain to the President's
Council on Bioethics. In a report* released last October,
the panel opined that "the prospect of preventing
(even) PTSD with beta-blockers or other memory-blunting
agents seems to be, for several reasons, problematic."
Among practical problems, the report says,
is knowing whom to treat. Victims don't exhibit symptoms
of PTSD, by definition, at the time of the event. Accident
witnesses might start demanding prescriptions, imperiling
their future testimony. In the future foreseen by the
council, doctors could "give beta-blockers liberally
to soldiers on the eve of combat, to emergency workers
en route to a disaster site, or even to individuals requesting
prophylaxis against the shame or guilt they might incur
from future misdeeds." The potential for misuse,
they claim, abounds.
Moreover, the report continues, bearing
traumatic memories is the moral obligation of those who
witness atrocities. Even if individual Holocaust survivors
were to benefit from treatments that weakened the memories
of their experiences, the council writes, society as a
whole might be badly served by having no witnesses whose
memories are unadulterated. "Our memory is not merely
our own; it is part of the fabric of the society in which
The council's report largely misses the
mark, says Arthur Caplan, a bioethicist at the University
of Pennsylvania in Philadelphia. Certainly society must
preserve the record of atrocities such as the Holocaust,
he says, but doing so doesn't require denying individuals
the benefits of therapeutic drugs: "The notion that
we need to have suffering martyrs among us is cruel and
The subtext of the council's argument, says
Caplan, seems to be that using drugs to manipulate memories--whatever
the content of the memories--is unnatural and therefore
morally suspect. "I don't accept that at all,"
he says. For one, it obliterates the line between treating
memory and mood disorders and using drugs for the selfish
pursuit of self-improvement. And if treating an infection
with antibiotics is OK, he asks rhetorically, why shouldn't
it be OK to use drugs to correct a problem with memory
or cognition? "It's a moral argument that, if turned
in in my undergraduate bioethics class, would pull a C."
Selectively erasing memories does indeed
raise ethical questions, says Joseph LeDoux, director
of the Center for the Neuroscience of Fear
and Anxiety in New York City. But that's always true of
science that pushes the bounds, he says: "If we're
successful in doing these sorts of things, it will raise
a societal debate about how far we want to go."
Original source: http://www.sciencemag.org/