Volume 85 Issue 36 | Web Exclusive
Issue Date: September 3, 2007

Cover Stories: Hold That Thought

Memory At Its Worst

Emotional memory gone awry leads to posttraumatic stress disorder
Department: Science & Technology | Collection: Life Sciences
These hypertension drugs are being tested as PTSD treatments.
These hypertension drugs are being tested as PTSD treatments.

Memories tend to be most vivid when they're associated with an emotional high or low, whether that's the pleasure of a first kiss or the terror sparked by the 2001 attack on the World Trade Center.

Few people would voluntarily erase a pleasant memory, but they'd surely be tempted to get rid of a scary one. Yet fear memories can be beneficial because they discourage repetition of the behavior that brought the person into danger.

Almost everyone who goes through a frightening, traumatic experience endures anxiety, stress, and hypervigilance for some time afterward. "If you get mugged on the subway, you may be scared to take the subway for a few weeks," says Craig M. Powell, a neurologist at the University of Texas Southwestern Medical Center. "But after about four weeks, most people are able to get back on the subway and everything's fine. It's not that they forget that they were mugged; it's just the emotional strength of that memory subsides over time."

But in a person who develops posttraumatic stress disorder (PTSD), the fear lasts for more than a month and can even persist for years. "Their memory is either too strong to begin with or doesn't extinguish normally," explains Powell, who studies the disorder.

Several factors influence whether a person who survives a traumatic event will develop PTSD. These factors include the severity of the trauma, the extent of injury, whether a loved one was threatened, the victim's degree of helplessness during the event, and the amount of support provided afterward, according to the National Center for Posttraumatic Stress Disorder at the Department of Veterans Affairs.

Approximately 8% of the U.S. population has PTSD in any given year, the center reports. Not surprisingly, the rate among former combat soldiers runs much higher. Some 30% of Vietnam veterans and 12-20% of Iraq war veterans have PTSD.

Those who suffer from the disorder "can't get what happened to them out of their mind," says Matthew J. Friedman, the center's executive director. "They can't forget the suicide bomber, the rape, the hurricane when they were almost killed or they witnessed awful things happening to someone else."

People with PTSD sometimes find that involuntary recall of the horrible event swamps their perception of current reality. "It's like being in a time machine," Friedman says. "All of a sudden, the present vanishes and I'm back in the alleyway where I was assaulted, or I'm back in Baghdad's Sadr City where I was attacked, or I'm back in the Ninth Ward in New Orleans where the levees were breached. And for the moment, I'm not here, I'm there. I'm terrified, and I'm worried about my life or my family's safety."

Because the memories are so intolerable, PTSD sufferers will do almost anything to elude them, Friedman says. A person who was attacked on an elevator will avoid using them; someone who was in a terrible head-on collision will avoid driving.

They'll also adopt psychological strategies to cope with PTSD. "For example, if I can't turn off the memory, I'll try to turn off the unbearable feelings that go with it. It's like psychological anesthesia," Friedman says. "The problem is, you can't be selective about this. If you turn down your capacity to feel terror, horror, guilt, and sadness, you also turn down your capacity to feel love, friendship, and enjoyment."

That's why so many marriages and interpersonal relationships are casualties of the disorder, Friedman adds. "You're wooden; you're dead inside. Things that you used to enjoy doing are no longer pleasurable. You think that your life might be snuffed out at any time because it almost was in the traumatic episode."

Although researchers have a pretty clear picture of the psychological impact of trauma, they're still trying to work out the details of the physiological impact.

Experiments by researchers, including Joseph E. LeDoux of New York University, show that when a traumatic memory is instilled in an animal, "a very large percentage of synapses becomes engaged in that memory, far larger than we previously suspected," says Alcino J. Silva, a neurobiologist at the University of California, Los Angeles. Synapses are junctions that connect one neuron to another in the brain. "Something like 20% of all the synapses in 20% of the cells in the amygdala", the brain sector that holds emotional and fear-associated memory, "become activated by that single memory," Silva says.

The traumatic memory is encoded in so many synapses and neurons that unrelated experiences occurring afterward can reactivate the same synapses, triggering recall of the traumatic events, Silva says.

"For example, a soldier comes home and there's a little problem with his job, his children, his wife, and all of a sudden all of this trauma, all of this anxiety, all of this unjustified reaction comes flooding in," Silva says. "The original experience involves such a large percentage of the real estate in the amygdala- it's like you buy so much of the property in a little village that you are likely to walk through that property no matter where you go in that village."

A traumatic experience prompts the amygdala to stimulate the adrenal glands to release adrenaline and noradrenaline. These hormones, which are also known as epinephrine and norepinephrine, respectively, in turn stimulate the amygdala to reinforce memories of the emotionally charged experience.

The traumatic experience also boosts the adrenal glands' production of cortisol, a stress hormone that initially enhances memory of the event. Each time a person subsequently recalls the event, the brain triggers release of another burst of cortisol from the adrenal glands. In normal people, these cortisol bursts gradually diminish the fearful nature of the memory, Powell believes. In contrast, evidence suggests that PTSD patients produce lower than normal levels of cortisol, so their traumatic memories retain emotional intensity over the long term, Powell says.

Powell and others have been studying mice to get a better handle on this mechanism. For these studies, researchers place a mouse in a box and give it a mild foot shock. If that experience is repeated, the mouse will come to fear the box, a technique known as fear conditioning.

Powell conducted a trial in which he administered corticosterone, the animal equivalent of cortisol, right after a conditioned mouse was placed back in the box it feared. Powell found that the animal's fear of the box diminished much more quickly than in conditioned mice that didn't receive corticosterone (J. Neurosci. 2006, 26, 9560).

Prior work by LeDoux and McGill University's Karim Nader showed that when memories are recalled, perhaps even if they are traumatic, they can be weakened, Silva says. Their findings helped revive interest in reconsolidation, the process by which a recalled memory is stored away again, much like putting a file back in a filing cabinet. Unless a memory is reconsolidated, it will be forgotten, just as a file can get lost if it's not returned to the filing cabinet. Memory loss is undesirable in some contexts, but for PTSD patients, this is "an area of great hope," Silva notes. In 2002, his own lab reported that inhibiting the protein CREB while reminding mice of a previously stored fear memory led the animals to forget that memory.

Several groups have more recently reported on techniques to ease or erase traumatic memories while leaving other memories intact. UT Southwestern neuroscientist James A. Bibb and colleagues found that traumatic memory can be damped more quickly than normal in mice lacking Cdk5, a kinase that phosphorylates a number of synaptic proteins and is involved in synaptic plasticity (Nat. Neurosci. 2007, 10, 880). The group showed that the enhanced extinction of traumatic memory might be related to Cdk5's control of NMDA receptor degradation.

LeDoux selectively wiped out a traumatic memory in rats by dosing the animals with an inhibitor of mitogen-activated protein (MAP) kinase, which is central to memory formation, just before reactivating the memory (Nat. Neurosci. 2007, 10, 414).

Likewise, inhibiting protein kinase A (PKA), another protein heavily involved in memory formation, disrupted reconsolidation of retrieved fear memories, according to Yale University psychiatrist Jane R. Taylor (Nat. Neurosci. 2006, 9, 167). On the other hand, increased activation of PKA enhanced the memories.

It will take years before such research can be translated into effective targeted treatments for PTSD. In the meantime, the disorder can be treated with psychotherapy. Two medications, the antidepressants Zoloft (sertraline) and Paxil (paroxetine), which raise the level of the neurotransmitter serotonin in the brain, have been approved for treating the disorder. Psychotherapy and antidepressants do not fully treat PTSD symptoms and do not work in all patients, Powell notes.

Friedman says a number of other available drugs are being tested, including antiepileptic drugs and mood stabilizers. The hypertension treatments prazosin and propranolol, which block the receptor for adrenaline and noradrenaline and therefore prevent these stress hormones from acting in the amygdala, are also under investigation.

As new PTSD treatments inch closer to market, society is wrestling with the implications. For instance, memory-altering drugs could be abused. Healthy people might take them to chase away woes that don't rise to the level of trauma, or criminals might administer them to people they've victimized.

Some opponents of treatments that lessen the impact of horrific memories contend that such memories are useful in discouraging criminal or violent behavior. They also maintain that a victim's traumatic memories, though disagreeable, are part of what shapes a person's character.

And just how far should a memory be unraveled? Some compounds apparently reduce the emotional weight of a traumatic memory, whereas others seem to erase the entire memory. Powell suggests that clinical trials of experimental compounds will be necessary to distinguish between these two mechanisms.

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