Sunday, October 12, 2014

Mind control

Here's a pre-edited version of my piece for the Observer today, with a little bit more stuff still in it and some links. This was a great topic to research, and a bit disconcerting at times too.


Be careful what you wish for. That’s what Joel, played by Jim Carrey, discovers in Charlie Kaufmann’s 2004 film Eternal Sunshine of the Spotless Mind, when he asks a memory-erasure company Lacuna Inc. to excise the recollections of a painful breakup from his mind. While the procedure is happening, Joel realizes that he doesn’t want every happy memory of the relationship to vanish, and seeks desperately to hold on to a few fragments.

The movie offers a metaphor for how we are defined by our memories, how poignant is both their recall and their loss, and how unreliable they can be. So what if Lacuna’s process is implausible? Just enjoy the allegory.

Except that selective memory erasure isn’t implausible at all. It’s already happening.

Researchers and clinicians are now using drugs to suppress the emotional impact of traumatic memories. They have been able to implant false memories in flies and mice, so that innocuous environments or smells seem to be “remembered” as threatening. They are showing that memory is not like an old celluloid film, fixed but fading; it is constantly being changed and updated, and can be edited and falsified with alarming ease.

“I see a world where we can reactivate any kind of memory we like, or erase unwanted memories”, says neuroscientist Steve Ramirez of the Massachusetts Institute of Technology. “I even see a world where editing memories is something of a reality. We’re living in a time where it’s possible to pluck questions from the tree of science fiction and ground them in experimental reality.” So be careful what you wish for.

But while it’s easy to weave capabilities like this into dystopian narratives, most of which the movies have already supplied – the authoritarian memory-manipulation of Total Recall, the mind-reading police state of Minority Report, the dream espionage of Inception – research on the manipulation of memory could offer tremendous benefits. Already, people suffering from post-traumatic stress disorder (PTSD), such as soldiers or victims of violent crime, have found relief from the pain of their dark memories through drugs that suppress the emotional associations. And the more we understand about how memories are stored and recalled, the closer we get to treatments for neurodegenerative conditions such as Alzheimer’s and other forms of dementia.

So there are good motivations for exploring the plasticity of memory – how it can be altered or erased. And while there are valid concerns about potential abuses, they aren’t so very different from those that any biomedical advance accrues. What seems more fundamentally unsettling, but also astonishing, about this work is what it tells us about us: how we construct our identity from our experience, and how our recollections of that experience can deceive us. The research, says Ramirez, has taught him “how unstable our identity can be.”

Best forgotten

Your whole being depends on memory in ways you probably take for granted. You see a tree, and recognize it as a tree, and know it is called “tree” and that it is a plant that grows. You know your language, your name, your loved ones. Few things are more devastating, to the individual and those close to them, than the loss of these everyday facts. As the memories fade, the person seems to fade with them. Christopher Nolan’s film Memento echoes the case of Henry Molaison, who, after a brain operation for epilepsy in the 1950s, lost the ability to record short-term memories. Each day his carers had to introduce themselves to him anew.

Molaison’s surgery removed a part of his brain called the hippocampus, giving a clue that this region is involved in short-term memory. Yet he remembered events and facts learnt long ago, and could be taught new ones, indicating that long-term memory is stored somewhere else. Using computer analogies for the brain is risky, but it’s reasonable here to compare our short-term memory with a computer’s ephemeral working memory or RAM, and the long-term memory with the hard drive that holds information more durably. While short-term memory is associated with the hippocampus, long-term memory is more distributed throughout the cortex. Some information is stored long-term, such as facts and events we experience repeatedly or that have an emotional association; other items vanish within hours. If you look up the phone number of a plumber, you’ll probably have forgotten it by tomorrow, but you may remember the phone number of your family home from childhood.

What exactly do we remember? Recall isn’t total – you might retain the key aspects of a significant event but not what day of the week it was, or what you were wearing, or exactly what was said. Your memories are a mixed bag: facts, feelings, sights, smells. Ramirez points out that, while Eternal Sunshine implies that all these features of a memory are bundled up and stored in specific neurons in a single location in the brain, in fact it’s now clear that different aspects are stored in different locations. The “facts”, sometimes called episodic memory, are filed in one place, the feelings in another (generally in a brain region called the amygdala). All the same, those components of the memory do each have specific addresses in the vast network of our billions of neurons. What’s more, these fragments remain linked and can be recalled together, so that the event we reconstruct in our heads is seamless, if incomplete. “Memory feels very cohesive, but in reality it’s a reconstructive process”, says Ramirez.

Given all this filtering and parceling out, it’s not surprising that memory is imperfect. “The fidelity of memory is very poor”, says psychologist Alain Brunet of McGill University in Montreal. “We think we remember exactly what happens, but research demonstrates that this is a fallacy.” It’s our need for a coherent narrative that misleads us: the brain elaborates and fills in gaps, and we can’t easily distinguish the “truth” from the invention. You don’t need fancy technologies to mess with memory – just telling someone they experienced something they didn’t, or showing them digitally manipulated photos, can be enough to seed a false conviction. That, much more than intentional falsehood, is why eye-witness accounts may be so unreliable and contradictory.

It gets worse. One of the most extraordinary findings of modern neuroscience, reported in 2000 by neurobiologist Joseph LeDoux and his colleagues at New York University, is that each time you remember something, you have to rebuild the memory again. LeDoux’s team reported that when rats were conditioned to associate a particular sound with mild electric shocks, so that they showed a “freezing” fear response when they heard the sound subsequently, this association could be broken by infusing the animals’ amygdala with a drug called anisomycin. The sound then no longer provoked fear – but only if the drug was administered within an hour or so of the memory being evoked. Anisomycin disrupts biochemical processes that create proteins, and the researchers figured that this protein manufacture was essential for restoring a memory after it has arisen. This is called reconsolidation: it starts a few minutes after recall, and takes a few hours to complete.

So those security questions asking you for the name of your first pet are even more bothersome than you thought, because each time you have to call up the answer (sorry if I just made you do it again), your brain then has to write the memory back into long-term storage. A computer analogy is again helpful. When we work on a file, the computer makes a copy of the stored version and we work on that – if the power is cut, we still have the original. But as Brunet explains, “When we remember something, we bring up the original file.” If we don’t write it back into the memory, it’s gone.

This rewriting process can, like repeated photocopying, degrade the memory a little. But LeDoux’s work showed that it also offers a window for manipulating the memory. When we call it up, we have the opportunity to change it. LeDoux found that a drug called propranolol can weaken the emotional impact of a memory without affecting the episodic content. This means that the effect of painful recollections causing PTSD can be softened. Propranolol is already known to be safe in humans: it is a beta blocker used to treat hypertension, and (tellingly) also to combat anxiety, because it blocks the action of the stress hormone epinephrine in the amygdala. A team at Harvard Medical School has recently discovered that xenon, the inert gas used as an anaesthetic, can also weaken the reconsolidation of fear memories in rats. An advantage of xenon over propranolol is that it gets in and out of the brain very quickly, taking about three minutes each way. If it works well for humans, says Edward Meloni of the Harvard team, “we envisage that patients could self-administer xenon immediately after experiencing a spontaneous intrusive traumatic memory, such as awakening from a nightmare.” The timing of the drug relative to reactivation of the trauma memory may, he says, be critical for blocking the reconsolidation process.

These techniques are now finding clinical use. Brunet uses propranolol to treat people with PTSD, including soldiers returned from active combat, rape victims and people who have suffered car crashes. “It’s amazingly simple,” he says. They give the patients a pill containing propranolol, and then about an hour later “we evoke the memory by having patients write it down and then read it out.” That’s often not easy for them, he says – but they manage it. The patients are then asked to continue reading the script regularly over the next several weeks. Gradually they find that its emotional impact fades, even though the facts are recalled clearly.

“After three or four weeks”, says Brunet, “our patients say things like ‘I feel like I’m smiling inside, because I feel like I’m reading someone else’s script – I’m no longer personally gripped by it.’” They might feel empathy with the descriptions of the terrible things that happened to this person – but that person no longer feels like them. No “talking cure” could do that so quickly and effectively, while conventional drug therapies only suppress the symptoms. “Psychiatry hasn’t cured a single patient in sixty years”, Brunet says.

These cases are extreme, but aren’t even difficult memories (perhaps especially those) part of what makes us who we are? Should we really want to get rid of them? Brunet is confident about giving these treatments to patients who are struggling with memories so awful that life becomes a torment. “We haven’t had a single person say ‘I miss those memories’”, he says. After all, there’s nothing unnatural about forgetting. “We are in part the sum of our memories, and it’s important to keep them”, Brunet says. “But forgetting is part of the human makeup too. We’re built to forget.”

Yet it’s not exactly forgetting. While propranolol and xenon can modify a memory by dampening its emotional impact, the memory remains: PTSD patients still recall “what happened”, and even the emotions are only reduced, not eliminated. We don’t yet really understand what it means to truly forget something. Is it ever really gone or just impossible to recall? And what happens when we learn to overcome fearful memories – say, letting go of a childhood fear of dogs as we figure that they’re mostly quite friendly? “Forgetting is fairly ill-defined”, says neuroscientist Scott Waddell at the University of Oxford. “Is there some interfering process that out-competes the original memory, or does the original memory disappear altogether?” Some research on flies suggests that forgetting isn’t just a matter of decay but an active process in which the old memory is taken apart. Animal experiments have also revealed the spontaneous re-emergence of memories after they were apparently eliminated by re-training, suggesting that memories don’t vanish but are just pushed aside. “It’s really not clear what is going on”, Waddell admits.

Looking into a fly’s head

That’s not so surprising, though, because it’s not fully understood how memory works in the first place. Waddell is trying to figure that out – by training fruit flies and literally looking into their brains. What makes flies so useful is that it’s easy to breed genetically modified strains, so that the role of specific genes in brain activity can be studied by manipulating or silencing them. And the fruit fly is big and complex enough to show sophisticated behavior, such as learning to associate a particular odour with a reward like sugar, while being simple enough to comprehend – it has around 100,000 neurons, compared to our many billions.

What’s more, a fruit fly’s brain is transparent enough to look right through it under the microscope, so that one can watch neural processing while the fly is alive. By attaching fluorescent molecules to particular neurons, Waddell can identify the neural circuitry linked to a particular memory. In his lab in Oxford he showed me an image of a real fly’s brain: a haze of bluish-coloured neurons, with bright green spots and filaments that are, in effect, a snapshot of a memory. The memory might be along the lines of “Ah, that smell – the last time I followed it, it led to something tasty.”

How do you find the relevant neurons among thousands of others? The key is that when neurons get active to form a memory, they advertise their state of busyness. They produce specific proteins, which can be tagged with other light-emitting proteins by genetic engineering of the respective genes. One approach is to inject benign viruses that stitch the light-emission genes right next to the gene for the protein you want to tag; another is to engineer particular cells to produce a foreign protein to which the fluorescent tags will bind. When these neurons get to work forming a memory, they light up. Ramirez compares it to the way lights in the windows of an office block at night betray the location of workers inside.

This ability to identify and target individual memories has enabled researchers like Waddell and Ramirez to manipulate them experimentally in, well, mind-boggling ways. Rather than just watching memories form by fluorescent tagging, they can use tags that act as light-activated switches to turn gene activity on or off with laser light directed down an optical fibre into the brain. This technique, called optogenetics, is driving a revolution in neuroscience, Ramirez says, because it gives researchers highly selective control over neural activity – enabling them in effect to stimulate or suppress particular thoughts and memories.

Waddell’s lab is not a good place to bring a banana for lunch. The fly store is packed with shelves of glass bottles, each full of flies feasting on a lump of sugar at the bottom. Every bottle is carefully labeled to identify the genetic strain of the insects it contains: which genes have been modified. But surely they get out from time to time, I wonder – and as if on cue, a fly buzzes past. Is that a problem? “They don’t survive for long on the outside,” Waddell reassures me.

Having spent the summer cursing the plague of flies gathering around the compost bin in the kitchen, I’m given fresh respect for these creatures when I inspect one under the microscope and see the bejeweled splendor of its red eyes. It’s only sleeping: you can anaesthetize fruit flies with a puff of carbon dioxide. That’s important for mapping neurons to memories in the microscope, because there’s not much going on in the mind of a dead fly.

These brain maps are now pretty comprehensive. We know, for example, which subset of neurons (about 2,000 in all) is involved in learning to recognize odours, and which neurons can give those smells good or bad associations. And thanks to optogenetics, researchers have been able to switch on some of these “aversive” neurons while flies smell a particular odour, so that they avoid it even though they have actually experienced nothing bad (such as shock treatment) in its presence – in other words, you might say, to stimulate a fictitious false memory. For a fly, it’s not obvious that we can call this “fear”, Waddell says, but “it’s certainly something they don’t like”. In the same way, by using molecular switches that are flipped with heat rather than light, Waddell and his colleagues were able to give flies good vibes about a particular smell. Flies display these preferences by choosing to go in particular directions when they are placed in little plastic mazes, some of them masterfully engineered with little gear-operated gates courtesy of the lab’s 3D printer.

Ramirez, working in a team at MIT led by Susumu Tonegawa, has practiced similar deceptions on mice. In an experiment in 2012 they created a fear memory in a mouse by putting it in a chamber where it experienced mild electric shocks to the feet. While this memory was being laid down, the researchers used optogenetic methods to make the corresponding neurons, located in the hippocampus, switchable with light. Then they put the mouse in a different chamber, where it seemed perfectly at ease. But when they reactivated the fear memory with light, the mouse froze: suddenly it had bad feelings about this place.

That’s not exactly implanting a false memory, however, but just reactivating a true one. To genuinely falsify a recollection, the researchers devised a more elaborate experiment. First, they placed a mouse in a chamber and labeled the neurons that recorded the memory of that place with optogenetic switches. Then the mouse was put in a different chamber and given mild shocks – but while these were delivered, the memory of the first chamber was triggered using light. When the mouse was then put back in the first chamber it froze. Its memory insisted, now without any artificial prompting, that the first chamber was a nasty place, even though nothing untoward had ever happened there. It is not too much to say that a false reality had been directly written into the mouse’s brain.

You must remember this

The problem with memory is often not so much that we totally forget something or recall it wrongly, but that we simply can’t find it even though we know it’s in there somewhere. What triggers memory recall? Why does a fly only seem to recall a food-related odour when it is hungry? Why do we feel fear only if we’re in actual danger, and not all the time? Indeed, it is the breakdown of these normal cues that produces PTSD, where the fear response gets triggered in inappropriate situations.

A good memory is largely about mastering this triggering process. Participants in memory competitions that involve memorizing long sequences of arbitrary numbers are advised to “hook” the information onto easily recalled images. A patient named Solomon Shereshevsky, studied in the early twentieth century by the neuropsychologist Alexander Luria, exploited his condition of synaesthesia – the crosstalk between different sensory experiences such as sound and colour – to tag information with colours, images, sounds or tastes so that he seemed able to remember everything he heard or read. Cases like this show that there is nothing implausible about Jorge Luis Borges’ fictional character Funes the Memorious, who forgets not the slightest detail of his life. We don’t forget because we run out of brain space, even if it sometimes feels like that.

Rather than constructing a complex system of mnemonics, perhaps it is possible simply to boost the strength of the memory as it is imprinted. “We know that emotionally arousing situations are more likely to be remembered than mundane ones”, LeDoux has explained. “A big part of the reason is that in significant situations chemicals called neuromodulators are released, and they enhance the memory storage process.” So memory sticks when the brain is aroused: emotional associations will do it, but so might exercise, or certain drugs. And because of reconsolidation, it seems possible to enhance memory after it has already been laid down. LeDoux has found that a chemical called isoproterenol has the opposite effect from propranolol on reconsolidation of memory in rats, making fear memories even stronger as they are rewritten into long-term storage in the amygdala. If it works for humans too, he speculates that the drug might help people who have “sluggish” memories.

Couldn’t we all do with a bit of that, though? Ramirez regards chemical memory enhancement as perfectly feasible in principle, and in fact there is already some evidence that caffeine can enhance long-term memory. But then what is considered fair play? No one quibbles about students going into an exam buoyed up by an espresso, but where do we draw the line?

Mind control

It’s hard to come up with extrapolations of these discoveries that are too far-fetched to be ruled out. You can tick off the movies one by one. The memory erasure of Eternal Sunshine is happening right now to some degree. And although so far we know only how to implant a false memory if it has actually been experienced in another context, as our understanding of the molecular and cellular encoding of memory improves Ramirez thinks it might be feasible to construct memories “from the ground up”, as in Total Recall or the implanted childhood recollections of the replicant Rachael in Blade Runner. As Rachael so poignantly found out, that’s the way to fake a whole identity.

If we know which neurons are associated with a particular memory, we can look into a brain and know what a person is thinking about, just by seeing which neurons are active: we can mind-read, as in Minority Report. “With sufficiently good technology you could do that”, Ramirez affirms. “It’s just a problem of technical limitations.” By the same token, we might reconstruct or intervene in dreams, as in Inception (Ramirez and colleagues called their false-memory experiment Project Inception). Decoding the thought processes of dreams is “a very trendy area, and one people are quite excited about”, says Waddell.

How about chips implanted in the brain to control neural activity, Matrix-style? Theodore Berger of the University of Southern California has implanted microchips in rats’ brains that can duplicate the role of the hippocampus in forming long-term memories, recording the neural signals involved and then playing them back. His most recent research shows that the same technique of mimicking neural signals seems to work in rhesus monkeys. The US Defense Advanced Research Projects Agency (DARPA) has two such memory-prosthesis projects afoot. One, called SUBNETS, aims to develop wireless implant devices that could treat PTSD and other combat-related disorders. The other, called RAM (Restoring Active Memories), seeks to restore memories lost through brain injury that are needed for specialized motor skills, such as how to drive a car or operate machinery. The details are under wraps, however, and it’s not clear how feasible it will be to record and replay specific memories. LeDoux professes that he can’t imagine how it could work, given that long-term memories aren’t stored in a single location. To stimulate all the right sites, says Waddell, “you’d have to make sure that your implantation was extremely specific – and I can’t see that happening.”

Ramirez says that it’s precisely because the future possibilities are so remarkable, and perhaps so unsettling, that “we’re starting this conversation today so that down the line we have the appropriate infrastructure.” Are we wise enough to know what we want to forget, to remember, or to think we remember? Do we risk blanking out formative, instructive and precious experiences, or finding ourselves one day being told, as Deckard tells Rachael in Blade Runner, “those aren’t your memories – they’re someone else’s”?

“The problems are not with the current research, but with the question of what we might be able to do in 10-15 years,” says Brunet. It’s one thing to bring in legislation to restrict abuses, just as we do for other biomedical technologies. But the hardest arguments might be about not what we prohibit but what we allow. Should individuals be allowed to edit their own memories or have false ones implanted? Ramirez is upbeat, but insists that the ethical choices are not for scientists alone to thrash out. “We all have some really big decisions ahead of us,” he says.


Chemdiary said...

Excellent! Thanks for this great post. Do you think we "remember" the answer for something very simple like "2X2" or do we actually do the math each time?

Unknown said...

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