The latest issue of Eureka, the Times’s monthly science supplement, is out today. I’ve been incredibly supportive of the venture and it’s great to see that a major national newspaper is increasing its science coverage, rather than cutting back on it. For this issue (the fourth, I think), I’ve written a piece on fear and memory, including a lot of research that I’ve previously covered in this blog.
While writing the piece, I interviewed a scientist called Todd Sacktor who’s doing some fascinating work in this field. Sacktor discovered that a protein called PKMzeta is vital for storing memory. Remove it, and memories are deleted, seemingly irreversibly. I’m printing the full transcript of the interview here, as a sort of companion piece to the Eureka feature. Think of it like one of the extras on a DVD.
These are the sorts of services that I think modern journalists can provide for their readers, to expand the boundaries of an article well beyond the first capital and the final fullstop. It won’t work in every case and time is obviously a factor, but there are exceptions when a scientist will be so eloquent and enthusiastic that it would be a crime not to print all of their words. There’s plenty of golden material here that didn’t make it to the final piece because of word limits or because it didn’t fit in the narrative. Here, you’ll hopefully get a fuller picture of PKMzeta. And for non-journalists, it might be interesting to see where I’ve pulled out quotes for the actual piece.
When people think about memory, they often think of discrete things like files on a computer that can be stored or lost. How do such metaphors stand now?
We think memories are stored by the action of PKMzeta at specific synapses. So the commonplace notion of files on a computer hard disk isn’t that far from the truth now. In a sense, it’s actually closer than the old neuroscientific explanation – that you have the growth of new synapses that, once grown, simply connect networks of neurons more strongly. It’s a bit like branches of a tree getting thicker or denser and that’s the memory – they are are now stronger because of these new physical connections.
But a computer hard disk, the structure is there. The hard disk has a certain size and certain places for the zeroes and ones, but you can store different information in the pattern of zeroes and ones. PKMzeta shows that it’s kind of a mix between these two notions. PKMzeta turns up at specific synapses after you learn something. The unique properties of this enzyme allow it to be active all the time (which is really unusual) and active at specific synapses, doubling the strength of those connections rather than their number. A synapse with PKMzeta is twice as strong as it otherwise would be.
Bringing an old memory back to mind would, you might think, strengthen it. But not so – when memories are recalled, they enter a surprisingly vulnerable state, when they can be reshaped or even rewritten. It takes a while for the memory to become strengthened anew, through a process called reconsolidation. Memories aren’t just written once, but every time we remember them.
This system allows us to rapidly update our memories with new information, for a more flexible and adaptable brain. It also means that the very act of remembering provides a valuable window of opportunity, during which memory can be manipulated. Now, a group of US scientists have done just that, exploiting this window to remove a simple fearful memory using fresh information, rather than drugs or invasive surgery.
Daniela Schiller from New York University trained volunteers to fear a coloured square by pairing it with a mild electric shock (the “acquisition” part of the graph below). The next day, Schiller reactivated their fear memories by once again showing them the shocking squares. When they did, their skin betrayed their nervousness by becoming better at conducting electricity, a sure sign that they were sweating.
Schiller then tried to extinguish their fearful responses with “extinction trials”, where they repeatedly saw the square without any shocks. This procedure ought to break the first day’s conditioning and it did temporarily (the “extinction” part of the graph below). But fear memories are harder to banish than that. On the third day, the volunteers were once again exposed to the scary squares, which, once again, sent most of them into a nervous sweat (the “re-extinction” part).
The only exceptions were the people whose memories of their conditioning had been reactivated 10 minutes before they went through the extinction training. If Schiller left a gap of 6 hours, or if she took the recruits straight into the extinction trials, they still reacted nervously to the squares. These results fit with the idea of reconsolidation, where remembering a memory provides a short window of opportunity for overwriting it. Doing so produces an anti-fear blockade that lasts much longer than 24 hours.
Schiller invited her volunteers back a year later, and 19 out of 65 returned. She gave them four shocks and showed them the coloured squares again – a powerful procedure that should have dramatically reinstated the fears they had been conditioned with a year before. But those whose fear memories had been overwritten didn’t succumb, while volunteers who previously belonged to the 6-hour or the no-reminder groups quickly started to get nervous again.
Best of all, Schiller found that the effect of the fear blockade was very specific. In a second experiment, she paired two squares of different colours (CSa and CSb in the graph below) with electric shocks. But she only reminded her volunteers about one of them before trying to wipe their fears away. And as predicted, a day later, only the fear memory that had been reactivated had been eventually blocked. While this is a fairly simplistic scenario, the specific nature of the effect is a must if any realistic application is to come of this one day. In real life, scary memories are associated with many possible triggers and not just coloured squares.
This study is a sequel. Earlier this year, Joseph Le Doux, whose lab Schiller works in, published similar results showing that the same technique was successful in rats. They conditioned rats to link a tone with electric shocks and then erased that memory in the same way that they did for the human volunteers – they reminded the rats of the tone to open the reconsolidation window, and then used the time to overwrite their conditioning using a shock-free tone. As with humans, the timing was crucial.
Other studies have used drugs to the same ends but many of these have been toxic. The only promising drug, the beta-blocker propanolol, was the star of a media circus earlier this year. Merel Kindt showed that propanolol could erase the emotional sting of a fearful memory. The research exploited reconsolidation windows, just as Schiller’s study did. By giving propanolol to people before they recalled a scary spider memory, Kindt could erase the fearful response it triggered.
Schiller says that it would be better to use methods that don’t involve drugs because of any potential side effects. But Kindt isn’t entirely convinced by these new experiments. She told me that a person’s sweaty skin tells you about whether they expect something bad to happen but not whether they’re afraid of it. In her experiment, she measured fearful responses by looking at the startle reflex – how strongly people blink to the terror in question.
Schiller may have more work to do to convince her critics but, at the very least, her study provides more evidence that reconsolidation is something that could be manipulated to treat anxiety disorders or PTSD. Drugs don’t have to be the solution – earlier this year, British researchers showed that playing Tetris can stop traumatic memories from consolidating in the first place. Perhaps the famously addictive game could be used to interfere with reconsolidation too.
Ironically enough, studies like these often provoke fear and panic that they will fall into the wrong hands. Outraged editorials often follow, chiding us that fearful memories are useful things to have because they remind us not to poke that tiger or touch that flame. Indeed, there’s evidence that our brain actively protects such memories, shielding them in a net of guardian molecules. Manipulating such systems is to play God with people’s mind.
But such criticisms miss the point. For a start, the benefits of remembering fearful experiences can often lead to the extreme drawbacks of anxiety or post-traumatic stress disorder. But perhaps most importantly, the entire point of reconsolidation is to allow the brain to incorporate new data into its existing framework. All these studies are doing is to give it the right information at the right time, nothing more than an advert or a classroom seeks to do.
Reference: Nature doi:10.1038/nature08637
More on memories:
In my final year of university, with exam deadlines looming and time increasingly fleeting, I considered recording some of my notes and playing them over while I was asleep. The concept of effectively gaining 6 extra hours of revision was appealing, but the idea didn’t stick – it took too long to record the information and the noise stopped me from sleeping in the first place. And the whole thing had a vague hint of daftness about it. But a new experiment suggests that the idea actually has some merit, showing that you can indeed strengthen individual memories by reactivating them as you snooze.
Sleep is a boon to newborn memories. Several experiments have shown that sleep can act as a mental cement that consolidates fragile memories into stable ones. But John Rudoy from Northwestern University wanted to see if this process could be taken even further by replaying newly learned information while people slept.
He asked a dozen volunteers to remember the positions of 50 different objects as they appeared on a screen. The items, from kittens to kettles, were all accompanied by a relevant noise, like a meow or a whistle. Shortly after, the recruits all had a short nap. As they slept, Rudoy played them the sounds for 25 of the objects, against a background of white noise. When the volunteers woke up, they had to place each of the 50 objects in the right position, and they were marked on how close they came to the actual target.
The results were very clear – the volunteers positioned the objects around 15% more accurately if they’d heard the relevant sounds while they slept. Although the sleep sounds didn’t work for everyone, the majority of the participants – 10 out of 12 – benefited in some way. And none of them knew they heard anything at all while they slept. When they were told this and asked to guess which sounds they heard, they didn’t do any better than chance.
To show that this isn’t just a general benefit of revision, whether conscious or not, Rudoy did a similar experiment. This time, his volunteers heard the noises after they had first seen the objects but while they were still awake. This group proved to be no better at remembering the items’ locations than those who didn’t hear the second round of sounds.
Finally, to understand what was going on in the brains of the slumbering recruits, Rudoy used electroencephalograms (EEG) to measure the electrical activity in the heads of 12 fresh volunteers. He showed that people who were better at remembering the objects’ positions after their nap were also those who showed the most brain activity when they heard the sounds Rudoy thinks that hearing the sounds during sleep prompted the brain to rehearse and strengthen associations between the objects and their locations.
Some people think that sleep improves memories in a general way, by making our brains more flexible and easing the incorporation of new information. But these simple experiments show that the benefits can be very specific indeed. It’s not only possible to strengthen specific and individual memories by providing the right triggers, but we get the opportunity to do so every single night.
More on sleep:
When we think of memory aids, we consider repeating what we’ve learned, using clever mnemonics, or breaking information down into bite-size chunks. But one of the best memory aids we have available to us is something we all do on a daily basis – sleep. Studies have found that sleep enhances our memories of facts and physical skills alike. It can even help us remember movements that we see others do.
But this only works within a short window. Ysbrand van der Werf from the Netherlands Institute of Neuroscience found that people who saw a video of someone tapping keys on a laptop remembered the sequence more accurately if they slept on it within 12 hours. Any longer than that, and the snoozing didn’t boost their recall.
Van der Werf showed the video to 128 volunteers and then tested them on either the same finger-tapping sequence or a different one. The gap between video and test was either 12 or 24 hours, and some of the volunteers were allowed to sleep during the interval while others were not.
If the test sequence didn’t match the ones they saw, all the recruits did equally well. But if the sequence was the same, those who managed to sleep within the first 12 hours stood out – they were 22% faster and made 42% fewer errors than their peers who either didn’t sleep or who slept later. They even improved whether they had their naps during the day or in the evening.
These results parallel those from experiments where people actually had a chance to practice new skills before their naps. The big difference here is that the improvements came only after watching movements rather than actually performing them.
Van der Werf confirmed that by taking great care to ensure that his volunteers weren’t actually trying out the keystrokes for themselves. While watching the video, they had to tap two different keys to keep their fingers busy. Van der Werf even measured the muscle activity in the arms of seven volunteers to rule out the possibility that they were making subtle, unnoticed finger movements.
If it’s not to do with practice, it’s not to do with memorising the digits themselves or the position of the keys either. If the volunteers just saw the numbers flash up on screen, or if they saw coloured squares light up in the same position as the relevant keys, they didn’t become more accurate or faster when they had to replicate the sequence. They needed to actually see someone else doing it.
Van der Werf thinks that the recruits probably imagined their finger movements while watching the video, even if they didn’t actually try them out. It may even involve the mirror neurons that fire when an individual performs an action and when it sees someone else doing the same action (although mirror neurons have only been properly found in monkeys, and not humans).
Either way, the results highlight the importance of a good sleep when people are trying to pick up new physical skills. This could be especially important for people who can’t possibly to practice the movements in question, such as those who have suffered a stroke or broken a limb. And clearly the most important implication is that the next time I see someone doing parkour, I will immediately lie down and have a little nap. When I wake up, I will be Batman. SCIENCE!
Reference: PNAS doi:10.1073_pnas.0901320106
More on memory:
Our mind often seems like a gigantic library, where memories are written on parchment and stored away on shelves. Once filed, they remain steadfast and inviolate over time, although some may eventually become dusty and forgotten.
Now, Reut Shema, Yadin Dudai and colleagues from the Weizmann Institute of Science have found evidence that challenges this analogy. According to their work, our memory is more like a dynamic machine – it requires a constant energy supply to work. Cut the power and memories are lost.
Shema found that the plug that powers our memories is an enzyme called PKMzeta. This molecule is vital for a process called long-term potentiation (LTP) where a the strength of a synapse – the connection between two nerve cells – is increased in the face of new experiences. This process, and thus PKMzeta, fuels the production and storage of new memories.
Shema demonstrated the importance of PKMzeta by inactivating it in the brains of rats. He trained the rats to avoid the taste of the artificial sweetener saccharin and then injected the part of their brains that control taste with a chemical called ZIP that stops PKMZeta from doing its thing.
The results were striking – ZIP erased the rodents’ memories of what they’d learnt. It even killed off the relevant memories when the rats were injected a month after their training. In human terms, that’s the equivalent of erasing memories that were several years old.
A couple of weeks ago, I wrote about propranolol, a drug that can erase the emotion of fearful memories. When volunteers take the drug before recalling a scary memory about a spider, it dulled the emotional sting of future recollections. It’s not, however, a mind-wiping pill in the traditional science-fiction sense, and it can’t erase memories as was so widely reported by the hysterical mainstream media.
The research that’s published today is a different story. Jin-Hee Han from the University of Toronto has indeed found a way to erase a specific fearful memory, but despite the superficial similarities, this is a very different story to the propranolol saga. For a start, Han worked in mice not humans. And unlike the propranolol researchers, who were interested in developing ways of treating people with post-traumatic stress disorder, Han’s goal was to understand how memories are stored in the brain. Erasing them was just a step towards doing that.
Han’s found that a protein called CREB is a molecular beacon that singles out neurons involved in remembering fearful experiences. When a rat experiences something scary, the CREB-neurons in a part of its brain called the amygdala are responsible for storing that memory – for producing what neuroscientists call its “trace”. When Han killed the amygdala’s CREB-neurons, he triggered selective amnesia in the rats, abolishing the specific fears they had been trained to feel. The memory loss was permanent.
This is a major piece of work. Scientists have long believed that memories are represented by specific collections of neurons. But these neurons don’t occur in a neat, tidy clump; they’re often widely spread out, which makes finding the cells that make up any particular memory incredibly challenging. Han has done this by using the CREB protein as a marker. And in doing so, he had highlighted the vital role of this protein in our memories.
I stress again that this isn’t about erasing memories in and of itself. Doing so is just a means to an end – identifying a group of neurons involved in storing a specific memory. For reasons that should become clear in this article, Han’s technique isn’t exactly feasible in humans! Whether this will stop the inevitable run-for-the-hills editorials is perhaps unlikely, but enough speculation: on with the details.
The mainstream media are just queuing up to fail in their reporting of the propranolol story from a couple of days ago. To reiterate:
Propranolol is commonly used to treat high blood pressure and prevent migraines in children. But Merel Kindt and colleagues from the University of Amsterdam have found that it can do much more. By giving it to people before they recalled a scary memory about a spider, they could erase the fearful response it triggered.
The critical thing about the study is that the entire memory hadn’t been erased in a typical sci-fi way. Kindt had trained the volunteers to be fearful of spidery images by pairing them with electric shocks. Even after they’d been given propranolol, they still expected to receive a shock when they saw a picture of a spider – they just weren’t afraid of the prospect. The drug hadn’t so much erased their memories, as dulled their emotional sting. It’s more like removing all the formatting from a Word document than deleting the entire file.
The drug is not a “memory-wiping pill” (Guardian). It cannot “erase bad/painful memories” (Sun/ Fox News/ Metro/ Daily Mail) and it won’t give you a “spotless mind” (Scotsman). Perhaps it’s unsurprising given that massive wire agencies said similar things. The Press Association led with claims that the drug can “erase fearful memories“. Reuters at least said more cautiously that it was a “step towards erasing bad memories“.
To quote the person who actually did the research (and thanks Merel for chiming in on the earlier post):
“There was no memory erasure, just elimination of the fearful response.”
The problem with all of this, of course, is that people have straw-manned the research and are falling over themselves to publish trite editorials that (a) are irrelevant to the actual study and (b) serve to stoke public outrage over an ethical dilemma of their own concoction.
There are exceptions. The Boston Globe got it right and has a brilliant bit at the end that lays out in four simple sentences the bottom line, cautions, what’s next, and where the research was published. It has however accompanied the article with an incongruous photo of a koala, presumably some sort of mix-up with the Australian bushfire story.
The mental health charity MIND released a long and well-considered statement, which showed that they had actually read the paper and understood the science. The charity’s CEO, Paul Farmer, said:
“This is fascinating research that could transform the treatment for phobias and post traumatic stress disorder. Around 10 million people in the UK have a phobia and about 3.5% of the population will be affected by post traumatic stress disorder at some point yet our understanding of how to treat these conditions is still limited. While we welcome any advancement in this field we should also exercise caution before heralding this as a miracle cure.
“Eradicating emotional responses is clearly an area we would need to be very careful about. It could affect people’s ability to respond to dangerous situations in the future and could even take away people’s positive memories. We would not want to see an ‘accelerated Alzheimer’s’ approach.
“We still have limited research on how to treat complex mental health problems, with the focus often on pharmacological solutions. Drugs are a somewhat sledgehammer approach and can have unintended consequences. We know from other psychiatric drugs, for example antipsychotics and antidepressants, that individuals react in hugely varied ways to treatments and are often vulnerable to unpleasant side effects.
“We would need to see much more research into the risks and benefits into this treatment before it becomes a reality.”
All of that was culled by the BBC into the following:
But British experts questioned the ethics of tampering with the mind.
Paul Farmer, chief executive of mental health charity Mind, said he was concerned about the “fundamentally pharmacological” approach to people with problems such as phobias and anxiety.
He said the procedure might also alter good memories and warned against an “accelerated Alzheimer’s” approach.
Do you think it carries the same meaning or sense?
The wiping of unwanted memories is a common staple of science-fiction and if you believe this weekend’s headlines, you might think that the prospect has just become a reality. The Press Association said that a “drug helps erase fearful memories“, while the ever-hyperbolic Daily Mail talked about a “pill to erase bad memories“. The comparisons to The Eternal Sunshine of the Spotless Mind were inevitable, but the actual study, while fascinating and important, isn’t quite the mind-wiper these headlines might have you believe.
The drug in question is propranolol, commonly used to treat high blood pressure and prevent migraines in children. But Merel Kindt and colleagues from the University of Amsterdam have found that it can do much more. By giving it to people before they recalled a scary memory about a spider, they could erase the fearful response it triggered.
The critical thing about the study is that the entire memory hadn’t been erased in a typical sci-fi way. Kindt had trained the volunteers to be fearful of spidery images by pairing them with electric shocks. Even after they’d been given propranolol, they still expected to receive a shock when they saw a picture of a spider – they just weren’t afraid of the prospect. The drug hadn’t so much erased their memories, as dulled their emotional sting. It’s more like removing all the formatting from a Word document than deleting the entire file. Congatulations to Forbes and Science News who actually got it right.
Kindt’s work hinges on the fact that memories of past fears aren’t as fixed as previously thought. When they are brought back to mind, proteins at the synapses – the junctions between two nerve cells – are broken down and have to be created from scratch. This process is called “reconsolidation” and scientists believe that it helps to incorporate new information into existing memories. The upshot is that when we recall old memories, they have to be rebuilt on some level, which creates an opportunity for changing them.
A few years ago, two American scientists managed to use propranolol to banish fearful responses in rats. They injected the animals in their amygdalae, a part of their brains involved in processing emotional memories. The drug didn’t stop a fearful memory from forming in the first place, but it did impair the memory when the rats tried to retrieve it. Now, Kindt has shown that the chemical has the same effect in humans.