July 13, 2013


Repairing Bad Memories (Stephen S. Hall, June 17, 2013, MIT Technology Review Magazine)

Traumatic memories can be debilitating and can lead to severe mental health problems.

It was a Saturday night at the New York Psychoanalytic Institute, and the second-floor auditorium held an odd mix of gray-haired, cerebral Upper East Side types and young, scruffy downtown grad students in black denim. Up on the stage, neuroscientist Daniela Schiller, a riveting figure with her long, straight hair and impossibly erect posture, paused briefly from what she was doing to deliver a mini-lecture about memory.

She explained how recent research, including her own, has shown that memories are not unchanging physical traces in the brain. Instead, they are malleable constructs that may be rebuilt every time they are recalled. The research suggests, she said, that doctors (and psychotherapists) might be able to use this knowledge to help patients block the fearful emotions they experience when recalling a traumatic event, converting chronic sources of debilitating anxiety into benign trips down memory lane. [...]

Decades of research had established that long-term memory consolidation requires the synthesis of proteins in the brain's memory pathways, but no one knew that protein synthesis was required after the retrieval of a memory as well--which implied that the memory was being consolidated then, too. Nader's experiments also showed that blocking protein synthesis prevented the animals from recalling the fearsome memory only if they received the drug at the right time, shortly after they were reminded of the fearsome event. If Nader waited six hours before giving the drug, it had no effect and the original memory remained intact. This was a big biochemical clue that at least some forms of memories essentially had to be neurally rewritten every time they were recalled.

When Schiller arrived at NYU in 2005, she was asked by Elizabeth Phelps, who was spearheading memory research in humans, to extend Nader's findings and test the potential of a drug to block fear memories. The drug used in the rodent experiment was much too toxic for human use, but a class of antianxiety drugs known as beta-adrenergic antagonists (or, in common parlance, "beta blockers") had potential; among these drugs was propranolol, which had previously been approved by the FDA for the treatment of panic attacks and stage fright. ­Schiller immediately set out to test the effect of propranolol on memory in humans, but she never actually performed the experiment because of prolonged delays in getting institutional approval for what was then a pioneering form of human experimentation. "It took four years to get approval," she recalls, "and then two months later, they took away the approval again. My entire postdoc was spent waiting for this experiment to be approved." ("It still hasn't been approved!" she adds.)

While waiting for the approval that never came, Schiller began to work on a side project that turned out to be even more interesting. It grew out of an offhand conversation with a colleague about some anomalous data described at meeting of LeDoux's lab: a group of rats "didn't behave as they were supposed to" in a fear experiment, Schiller says.

The data suggested that a fear memory could be disrupted in animals even without the use of a drug that blocked protein synthesis. Schiller used the kernel of this idea to design a set of fear experiments in humans, while Marie-H. Monfils, a member of the LeDoux lab, simultaneously pursued a parallel line of experimentation in rats. In the human experiments, volunteers were shown a blue square on a computer screen and then given a shock. Once the blue square was associated with an impending shock, the fear memory was in place. Schiller went on to show that if she repeated the sequence that produced the fear memory the following day but broke the association within a narrow window of time--that is, showed the blue square without delivering the shock--this new information was incorporated into the memory.

Here, too, the timing was crucial. If the blue square that wasn't followed by a shock was shown within 10 minutes of the initial memory recall, the human subjects reconsolidated the memory without fear. If it happened six hours later, the initial fear memory persisted. Put another way, intervening during the brief window when the brain was rewriting its memory offered a chance to revise the initial memory itself while diminishing the emotion (fear) that came with it. By mastering the timing, the NYU group had essentially created a scenario in which humans could rewrite a fearsome memory and give it an unfrightening ending. And this new ending was robust: when Schiller and her colleagues called their subjects back into the lab a year later, they were able to show that the fear associated with the memory was still blocked.

The study, published in Nature in 2010, made clear that reconsolidation of memory didn't occur only in rats.

As a scientific idea, memory reconsolidation seems to be here to stay. Schiller notes that when she first started going to the massive annual meeting of the Society for Neuroscience a decade ago, she was lucky to see a single poster about reconsolidation theory. "Now," she says, "it's like entire alleys in the exhibition hall."

More important, Schiller's work has been quickly replicated and extended. Thomas Agren and colleagues at Uppsala University in Sweden confirmed last year that disrupting reconsolidation when humans reactivated a fear memory effectively abolished its fearsome effect; the group also showed through brain imaging in these volunteers that the amygdala was the locus of the changed memory. Yan-Xue Xue of Peking University in Beijing and colleagues reported last year that they had used nonpharmacological memory manipulation to help heroin addicts rewrite their association of environmental cues with a craving for the drug; the researchers said the effect lasted at least half a year, which was the length of the study.

Since moving uptown from NYU to Mount Sinai in 2010, Schiller has embarked on a new set of experiments exploring the clinical potential of memory reconsolidation. That in part explains why she shares her ninth-floor office with a tarantula, which sits in a cage under her desk. Called Web 2.0 (the name was bestowed by a member of Schiller's research group, a former writer on Saturday Night Live), the spider plays a role in ongoing experiments to block arachnophobia (fear of spiders) in humans without any drugs. "We are looking at the neural mechanisms of reconsolidation," she says. Those mechanisms--at both the synaptic level and the level of the whole brain--are fairly well understood in animals but not so easy to study in humans. "There are basically only two things you can do," she continues. "One is to do pharmacological studies, and the other is to look at brain function in an MRI as people update memories." They hope to publish findings on both fronts in the near future.

The reconstitution of memory has enormous therapeutic potential. Administering drugs like propranolol within hours of a traumatic experience might modify or minimize the long-term emotional impact of the memory. But if that's not possible, the memory might be modified later, when the experience is recalled in a safe, unthreatening context. Roger Pitman of Harvard Medical School, Karim Nader (now at McGill University), and their colleagues have reported that giving propranolol to people as they recall a traumatic experience can attenuate the emotional impact of the memory, giving hope for treatment of anxiety disorders like PTSD. Schiller views this as very promising. "If you miss intervening a few hours after the event," she says, "you still have other opportunities to intervene."

In some ways, the potential cultural impact and personal implications of reconsolidation are even more staggering. To put it in an extreme way, if we are all rewriting our memories every time we recall an event, the memory exists not as a file in our brain but only as the most recent rewrite of a scenario. Every memoir is fabricated, and the past is nothing more than our last retelling of it. Archival memory data is mixed with whatever new information helps shape the way we think--and feel--about it. "My conclusion," says Schiller, "is that memory is what you are now. Not in pictures, not in recordings. Your memory is who you are now."

In Schiller's view, then, the secret to preserving a memory doesn't lie in protein synthesis in the synapses or the shuttling of neural traffic from the hippocampus to the exurbs of the brain. Rather, she believes, memory is best preserved in the form of a story that collects, distills, and fixes both the physical and the emotional details of an event. "The only way to freeze a memory," she says, "is to put it in a story." 

Posted by at July 13, 2013 6:25 AM

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