Erase Your Fear
WHY YOU SHOULD CARE
Because promising new research into memory and emotion suggests that a drug could make therapy for PTSD patients work better, faster.
By Melissa Pandika
Richard Bjork returned home to Illinois after two terms of duty in Vietnam more than 40 years ago, but he still sees the bodies. He remembers how Vietcong solders rounded up and executed villagers suspected of sympathizing with the Americans–sometimes entire families, including children–leaving them to rot in the street.
Some corpses bloated like balloons in the sweltering, hundred-degree heat, while others lay engulfed in flies and maggots. Bjork, who was about 19 back then, took the time to bury them. For decades, they visited him in nightmares or in flashbacks during the day. “You see them, you smell them. You cry over them,” he says. “There’s times I’ve talked to the dead or tried to. I think we both end up wondering, why? ” Although liquor helped suppress the memories, they flooded back to haunt him as soon as he sobered up.
Half of PTSD patients who undergo exposure therapy don’t get better.
Anxiety and alcohol use made it nearly impossible for Bjork to hold down a job, and he attempted suicide countless times. He couldn’t figure out what was wrong, until someone suggested he might have post-traumatic stress disorder, or PTSD. In the 1980s, he began attending a weekly therapy group for combat veterans with the disorder. Although he’s not “cured,” he’s learned not to fear his memories as much, so he can finally make sense of them.
Bjork is one of about 7.7 million Americans who suffer from PTSD , a condition marked by intense anxiety stemming from dangerous, catastrophic events, such as war, natural disasters or abuse. People with PTSD often experience nightmares, flashbacks and a constant, heightened state of vigilance. One of the only effective treatments is exposure therapy, in which patients recount their memories in a safe environment, learning to reduce the fear associated with them over the course of about 2 to 3 months. Still, half of those who undergo exposure therapy don’t get better. But a study led by MIT neuroscientist Li-Huei Tsai suggests that an experimental drug called CI-994 might make therapy work better and faster. Earlier this year, Tsai’s group reported in the journal Cell that injecting mice with just one dose of CI-994 made the emotional context of even old, deeply entrenched memories more pliable.
Tsai notes that CI-994 doesn’t erase traumatic memories, but makes it easier to erase the fear associated with them through therapy. “You can recall the memory, but you don’t have the bad emotions,” explained Eileen Ahearn, a psychiatrist who works with veterans suffering from PTSD at William S. Middleton Veterans Affairs Hospital in Madison, Wisconsin.
Tsai’s study focused on an enzyme called HDAC2, which silences genes. In 2012, she showed that HDAC2 was on overdrive in mice with Alzheimer’s-like symptoms. She wondered whether HDAC2 also played a role in how traumatic memories lock themselves into brain circuits. To find out, she modeled PTSD in mice, training them to fear a particular chamber by placing them inside and administering a mild electrical shock. Then she gave them the mouse equivalent of exposure therapy–placing them in the same chamber, but without shocking them—either one day or 30 days later.
About 65 percent of PTSD patients also battle subtance abuse , and soldiers who suffer from the disorder are six times more likely to commit suicide than those who don’t .
Mice that underwent therapy a day later no longer responded fearfully to the chamber. Sure enough, the HDAC2 silencing enzyme was no longer running in their brain cells, meaning the so-called plasticity genes needed to make memories more vulnerable to modification could turn on.
But mice treated with therapy 30 days after the traumatic event still feared the chamber, even in the absence of an electrical shock. HDAC2 remained active, turning off plasticity genes. As a result, their memories were inflexible, too tightly associated with emotional response and resistant to being remolded. What’s needed to make therapy effective are malleable memories that can be formed into new shapes like soft plastics. Plasticity genes might be similarly silenced in PTSD patients who experienced trauma long ago, which could explain why they often don’t respond to therapy.
Tsai ran control experiments to ensure that CI-994 altered only the memory of the electrical shock—and no other memories.
Shortly after re-exposing the mice with 30-day old traumatic memories to the chamber, Tsai injected them with a protein called CI-994, which inhibits HDAC2—and the results floored her. The mice no longer froze in fear. “We were really, really surprised,” she said. HDAC2 had turned off a group of key neuroplasticity genes—but blocking HDAC2 with CI-994 turned them back on.
The mice experienced no side effects. What’s more, Tsai ran several control experiments to ensure that CI-994 altered only the memory of the electrical shock—and no other memories.
Tsai also paired an electrical shock with a musical tone. After the mice underwent exposure therapy with the chamber, she played the musical tone; they still froze in fear.
Although Tsai believes that “CI-994 is very promising,” only a clinical trial can reveal whether it works in human patients. It’s also not clear how long its effects last. If proven to work in humans, the drug will probably be used alongside therapy, “diminishing fear at an even faster rate,” says Ahearn, who wasn’t involved in the research.
But others are wary. Bjork and other veterans are hesitant to completely wipe out the fear associated with their traumatic memories, arguing that it’s shaped their identity.“[Us Vietnam War vets] had to live with this situation for 40 some years and, sad to say, that has made us who we are today,” Bjork said.
CI-994 is one of a few PTSD drugs under study. The U.S. Navy, for example, is recruiting participants for a clinical trial of an injection into the nerve tissue at the base of the neck. But some experts question whether a shot can truly cure PTSD. “There is no quick fix ,” wrote Kali Tal, scientific editor for the Institute of Social and Preventive Medicine at the University of Bern. “There is only the slow fix: stopping violence before it starts.” Many people with PTSD also have other hard-to-treat disorders like depression; in fact, PTSD and depression reinforce one another.
But for the millions who already have the disorder, drugs like CI-994 offer hope. Those whose symptoms make leaving the house a battle might welcome a respite—even a “quick fix.”
Tsai’s findings are bringing us a step closer to unlocking how our minds store memory and trigger feelings, tracing them to a dynamic interplay among genes, neural circuitry, our environment and other factors. She and other researchers have only just scratched the surface, but the payoff—a comprehensive understanding of how the brains works, and when it goes haywire—could help the millions who suffer from neuropsychiatric disorders regain control of their lives.
- Melissa PandikaContact Melissa Pandika