Roots of intuition: Even though PTSD is triggered by a stressful incident, it is really a disfunction of memory.
None of this is true. In the past decade, we have come to realise that our memories are not inert packets of data and they don’t remain constant. Even though every memory feels like an honest representation, that sense of authenticity is the biggest lie of all.
The very act of remembering changes the memory itself. Every time we recall an event, the structure of that memory in the brain is altered in light of the present moment, warped by our current feelings and knowledge. That’s why pushing to remember a traumatic event so soon after it occurs doesn’t unburden us; it reinforces the fear and stress that are part of the recollectionOne week later, all the patients returned to the lab and were exposed once again to a description of the traumatic event. Here’s where things got interesting: Subjects who got the placebo demonstrated levels of arousal consistent with PTSD (for example, their heart rate spiked suddenly), but those given propranolol showed significantly lower stress responses. Although they could still remember the event in vivid detail, the emotional memory located in the amygdala had been modified. The fear wasn’t gone, but it no longer seemed crippling. “The results we get sometimes leave me in awe,” Brunet says. “These are people who are unable to lead normal lives, and yet after just a few sessions they become healthy again.”Photo illustration: Curtis Mann; Photo: Ed Andrieski/AP
Recoveries are possible, but they aren’t necessarily neat. One of Brunet’s patients was Lois, a retired member of the Canadian military living in Kingston, Ontario. (She asked that I not use her last name.) When Lois describes the tragic arc of her life, she sounds like a cursed character in the Old Testament. Sexually molested as a child, she married an abusive man, who would later hang himself at home. Years after that, her teenage daughter was hit by a truck and died. “I’d been holding it together my entire life,” she says. “But when I heard my child was gone I just started sobbing and couldn’t stop. I felt this pain that I thought was going to kill me.”
Lois coped by drinking. She would start around noon and keep going until she went to bed. “I lost four years to alcohol,” she says. “But if I wasn’t drunk then I was crying. I knew I was killing myself, but I didn’t know what else to do.”
“Psychiatry never cures anything—all we do is treat the worst symptoms. But this new treatment could be the first psychiatric cure ever.”
In early 2011, Lois learned about the experimental trials being conducted by Brunet. She immediately wrote him an email, begging for help. “I’d spent a lot of my life in standard talk therapy,” she says. “It just didn’t do it for me. But this seemed like it might actually work.” Last spring Lois began reconsolidation treatment at Brunet’s hospital, driving to Montreal once a week. The routine was always the same: A nurse would give her propranolol, wait for the drug to take effect, and then have her read her life story out loud. The first few weeks were excruciating. “I was a mess for days afterward,” she says. “I couldn’t believe I’d signed up for this.” But then, after five weeks of therapy, Lois felt herself slowly improve. She would still cry when describing the death of her daughter—Lois cried during our interview—but now she could stop crying. “That was the difference,” she says. “I still remembered everything that happened, and it still hurt so much, but now I felt like I could live with it. The feelings were just less intense. The therapy let me breathe.”
Such improvements, small though they may seem, are almost unheard of in psychiatry. “We never cure anything,” Brunet says. “All we do is try to treat the worst symptoms. But I think this treatment has the potential to be the first psychiatric cure ever. For many people, the PTSD really is gone.”
Propranolol, of course, is an imperfect drug, a vintage tool commandeered for a new purpose. Despite Brunet’s optimistic assessment, many of his patients remain traumatized, albeit perhaps less so. While he is currently conducting a larger-scale, randomized PTSD trial with the beta-blocker, future therapies will rely on more targeted compounds. “These norepinephrine inhibitors are just what’s available right now,” LeDoux says. “They work OK, but their effect is indirect.” What reconsolidation therapy really needs is a drug that can target the fear memory itself. “The perfect drug wouldn’t just tamp down the traumatic feeling,” he says. “It would erase the actual representation of the trauma in the brain.”
Here’s the amazing part: The perfect drug may have already been found.
The chemistry of the brain is in constant flux, with the typical neural protein lasting anywhere from two weeks to a few months before it breaks down or gets reabsorbed. How then do some of our memories seem to last forever? It’s as if they are sturdier than the mind itself. Scientists have narrowed down the list of molecules that seem essential to the creation of long-term memory—sea slugs and mice without these compounds are total amnesiacs—but until recently nobody knew how they worked.
In the 1980s, a Columbia University neurologist named Todd Sacktor became obsessed with this mental mystery. His breakthrough came from an unlikely source. “My dad was a biochemist,” Sacktor says. “He was the one who said I should look into this molecule, because it seems to have some neat properties.” Sacktor’s father had suggested a molecule called protein kinase C, an enzyme turned on by surges of calcium ions in the brain. “This enzyme seemed to have a bunch of properties necessary to be a regulator of long-term potentiation,” Sacktor says. “But so did a bunch of other molecules. It took me a few years to figure out if my dad was right.”
In fact, it took Sacktor more than a decade. (He spent three years just trying to purify the molecule.) What he discovered is that a form of protein kinase C called PKMzeta hangs around synapses, the junctions where neurons connect, for an unusually long time. And without it, stable recollections start to disappear. While scientists like Nader had erased memories using chemicals that inhibited all protein synthesis, Sacktor was the first to target a single memory protein so specifically. The trick was finding a chemical that inhibited PKMzeta activity. “It turned out to be remarkably easy,” Sacktor says. “All we had to do was order this inhibitor compound from the chemical catalog and then give it to the animals. You could watch them forget.”
What does PKMzeta do? The molecule’s crucial trick is that it increases the density of a particular type of sensor called an AMPA receptor on the outside of a neuron. It’s an ion channel, a gateway to the interior of a cell that, when opened, makes it easier for adjacent cells to excite one another. (While neurons are normally shy strangers, struggling to interact, PKMzeta turns them into intimate friends, happy to exchange all sorts of incidental information.) This process requires constant upkeep—every long-term memory is always on the verge of vanishing. As a result, even a brief interruption of PKMzeta activity can dismantle the function of a steadfast circuit.
If the genetic expression of PKMzeta is amped up—by, say, genetically engineering rats to overproduce the stuff—they become mnemonic freaks, able to convert even the most mundane events into long-term memory. (Their performance on a standard test of recall is nearly double that of normal animals.) Furthermore, once neurons begin producing PKMzeta, the protein tends to linger, marking the neural connection as a memory. “The molecules themselves are always changing, but the high level of PKMzeta stays constant,” Sacktor says. “That’s what makes the endurance of the memory possible.”
For example, in a recent experiment, Sacktor and scientists at the Weizmann Institute of Science trained rats to associate the taste of saccharin with nausea (thanks to an injection of lithium). After just a few trials, the rats began studiously avoiding the artificial sweetener. All it took was a single injection of a PKMzeta inhibitor called zeta-interacting protein, or ZIP, before the rats forgot all about their aversion. The rats went back to guzzling down the stuff.
By coupling these amnesia cocktails to the memory reconsolidation process, it’s possible to get even more specific. Nader, LeDoux, and a neuroscientist named Jacek Debiec taught rats elaborate sequences of association, so that a series of sounds predicted the arrival of a painful shock to the foot. Nader calls this a “chain of memories”—the sounds lead to fear, and the animals freeze up. “We wanted to know if making you remember that painful event would also lead to the disruption of related memories,” Nader says. “Or could we alter just that one association?” The answer was clear. By injecting a protein synthesis inhibitor before the rats were exposed to only one of the sounds—and therefore before they underwent memory reconsolidation—the rats could be “trained” to forget the fear associated with that particular tone. “Only the first link was gone,” Nader says. The other associations remained perfectly intact. This is a profound result. While scientists have long wondered how to target specific memories in the brain, it turns out to be remarkably easy: All you have to do is ask people to remember them.
This isn’t Eternal Sunshine of the Spotless Mind-style mindwiping. In some ways it’s potentially even more effective and more precise. Because of the compartmentalization of memory in the brain—the storage of different aspects of a memory in different areas—the careful application of PKMzeta synthesis inhibitors and other chemicals that interfere with reconsolidation should allow scientists to selectively delete aspects of a memory. Right now, researchers have to inject their obliviating potions directly into the rodent brain. Future treatments, however, will involve targeted inhibitors, like an advanced version of ZIP, that become active only in particular parts of the cortex and only at the precise time a memory is being recalled. The end result will be a menu of pills capable of erasing different kinds of memories—the scent of a former lover or the awful heartbreak of a failed relationship. These thoughts and feelings can be made to vanish, even as the rest of the memory remains perfectly intact. “Reconsolidation research has shown that we can get very specific about which associations we go after,” LeDoux says. “And that’s a very good thing. Nobody actually wants a totally spotless mind.”
The astonishing power of PKMzeta forces us to redefine human memory. While we typically think of memories as those facts and events from the past that stick in the brain, Sacktor’s research suggests that memory is actually much bigger and stranger than that. In fact, PTSD isn’t the only disease that’s driven by a broken set of memories—other nasty afflictions, including chronic pain, obsessive-compulsive disorder, and drug addiction, are also fuelled by memories that can’t be forgotten.
Sacktor is convinced that the first therapeutic use of PKMzeta inhibitors will involve making people forget not an event but physical pain. For reasons that remain mysterious, some sensory nerves never recover from bodily injury; even after a wound heals, the hurt persists. The body remembers. Because these memories are made of the exact same stuff as every other kind of memory, injecting an inhibitor near the spinal cord—where, presumably, the sensation of pain is being stored—and then somehow inducing or focusing on the pain could instantly erase the long-term suffering, as if the nerves themselves were reset. “It’s hard to argue against this form of memory alteration,” Sacktor says. “It might be the only way to treat neuropathic pain.” PTSD is the emotional version of this problem. Instead of the pain coming from the spinal cord, it comes from the amygdala, where a trauma is encoded and just won’t let go. For many reconsolidation researchers, there is little difference among categories of hurt. It doesn’t matter if the tragedy is physical or psychic: The treatment is the same.
There is perhaps no societal plague more expensive than drug addiction. In the US, the overall cost of substance abuse exceeds $600 billion a year. Previous attempts to treat drug addiction with drugs have largely failed; methadone is among the best, and it’s not that good. But addiction is driven by memory—associating the high with a crack pipe, or the buzz of nicotine with the smell of smoke—which means that reconsolidation therapy offers some hope. Studies of morphine-addled rats have found that a few doses of a PKMzeta inhibitor can eliminate their cravings. Nader, meanwhile, has just begun a trial in which cocaine addicts are given propranolol and then shown a drug-related cue, such as a video of people shooting up. Because the blood-pressure medicine dials down their basic emotional response to the world—it reduces symptoms of stress but also inhibits expressions of pleasure—Nader believes it can slowly diminish the desire for illicit substances. “The craving is a learned association,” he says. “We’re hoping to weaken that association over time.”
Being able to control memory doesn’t simply give us admin access to our brains. It gives us the power to shape nearly every aspect of our lives. There’s something terrifying about this. Long ago, humans accepted the uncontrollable nature of memory; we can’t choose what to remember or forget. But now it appears that we’ll soon gain the ability to alter our sense of the past.
The problem with eliminating pain, of course, is that pain is often educational. We learn from our regrets and mistakes; wisdom is not free. If our past becomes a playlist—a collection of tracks we can edit with ease—then how will we resist the temptation to erase the unpleasant ones? Even more troubling, it’s easy to imagine a world where people don’t get to decide the fate of their own memories. “My worst nightmare is that some evil dictator gets ahold of this,” Sacktor says. “There are all sorts of dystopian things one could do with these drugs.” While tyrants have often rewritten history books, modern science might one day allow them to rewrite us, wiping away genocides and atrocities with a cocktail of pills.
Those scenarios aside, the fact is we already tweak our memories—we just do it badly. Reconsolidation constantly alters our recollections, as we rehearse nostalgias and suppress pain. We repeat stories until they’re stale, rewrite history in favor of the winners, and tamp down our sorrows with whiskey. “Once people realize how memory actually works, a lot of these beliefs that memory shouldn’t be changed will seem a little ridiculous,” Nader says. “Anything can change memory. This technology isn’t new. It’s just a better version of an existing biological process.”
It’s a pretty notion—hey, this memory-alteration stuff is totally natural, man—but some ethicists and clinicians dispute whether this kind of therapy is acceptable. Researchers in the field counter that not treating suffering is cruel, regardless of the type of pain involved. We have a duty, they say, to take psychological pain seriously. We can no longer ignore people like Lois. “If you’re in a car accident and you break your leg, everyone agrees we need to give you treatment and painkillers,” Nader says. “But if something terrible happens and your mind breaks, people conclude that treatment is a dangerous idea, at least if it’s effective. But what’s the difference?” Just think of all the poor souls in therapy, trying to talk themselves into a better place. These scientists point out that memory tweaks will one day be used in the same way—except that unlike CISD or Jungian analysis or selective serotonin reuptake inhibitors, these therapies could put permanent recovery just one pill away.
At the moment, of course, such treatments remain entirely hypothetical, an avant-garde limited to the lab. PKMzeta inhibitors can zap rodent memories, but we can’t ask the rats how they feel afterward. Maybe they feel terrible. Maybe they miss their fear. Maybe they miss their morphine. Or maybe all they know is that they miss something. They just can’t remember what.
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