Posts Tagged ‘memory’

Everyday experience makes it obvious – sometimes frustratingly so – that our working memory capacity is limited. We can only keep so many things consciously in mind at once. The results of a new study may explain why: They suggest that the “coupling,” or synchrony, of brain waves among three key regions breaks down in specific ways when visual working memory load becomes too much to handle.

“When you reach capacity there is a loss of feedback coupling,” said senior author Earl Miller, Picower Professor of Neuroscience at MIT’s Picower Institute for Learning and Memory. That loss of synchrony means the regions can no longer communicate with each other to sustain working memory.

Maximum working memory capacity – for instance the total number of images a person can hold in working memory at the same time – varies by individual but averages about four, Miller said. Researchers have correlated working memory capacity with intelligence.

Understanding what causes working memory to have an intrinsic limit is therefore important because it could help explain the limited nature of conscious thought and optimal cognitive performance, Miller said.

And because certain psychiatric disorders can lower capacity, said Miller and lead author Dimitris Pinotsis, a research affiliate in Miller’s lab, the findings could also explain more about how such disorders interfere with thinking.

“Studies show that peak load is lower in schizophrenics and other patients with neurological or psychiatric diseases and disorders compared to healthy people,” Pinotsis said. “Thus, understanding brain signals at peak load can also help us understand the origins of cognitive impairments.”

The study’s other author is Timothy Buschman, assistant professor at the Princeton University Neuroscience Institute and a former member of the Miller lab.

The new study published in the journal Cerebral Cortex is a detailed statistical analysis of data the Miller lab recorded when animal subjects played a simple game: They had to spot the difference when they were shown a set of squares on a screen and then, after a brief blank screen, a nearly identical set in which one square had changed color. The number of squares involved, hence the working memory load of each round, varied so that sometimes the task exceeded the animals’ capacity.

As the animals played, the researchers measured the frequency and timing of brain waves produced by ensembles of neurons in three regions presumed to have an important – though as yet unknown – relationship in producing visual working memory: the prefrontal cortex (PFC), the frontal eye fields (FEF), and the lateral intraparietal area (LIP).

The researchers’ goal was to characterize the crosstalk among these three areas, as reflected by patterns in the brain waves, and to understand specifically how that might change as load increased to the point where it exceeded capacity.

Though the researchers focused on these three areas, they didn’t know how they might work with each other. Using sophisticated mathematical techniques, they tested scores of varieties of how the regions “couple,” or synchronize, at high- and low-frequencies. The “winning” structure was whichever one best fit the experimental evidence.

“It was very open ended,” Miller said. “We modeled all different combinations of feedback and feedforward signals among the areas and waited to see where the data would lead.”

They found that the regions essentially work as a committee, without much hierarchy, to keep working memory going. They also found changes as load approached and then exceeded capacity.

“At peak memory load, the brain signals that maintain memories and guide actions based on these memories, reach their maximum,” Pinotsis said. “Above this peak, the same signals break down.”

In particular, above capacity the PFC’s coupling to other regions at low frequency stopped, Miller said.

Other research suggests that the PFC’s role might be to employ low-frequency waves to provide the feedback the keeps the working memory system in synch. When that signal breaks down, Miller said, the whole enterprise may as well. That may explain why memory capacity has a finite limit. In prior studies, he said, his lab has observed that the information in neurons degrades as load increases, but there wasn’t an obvious cut-off where working memory would just stop functioning.

“We knew that stimulus load degrades processing in these areas, but we hadn’t seen any distinct change that correlated with reaching capacity,” he said. “But we did see this with feedback coupling. It drops off when the subjects exceeded their capacity. The PFC stops providing feedback coupling to the FEF and LIP.”

Two sides to the story

Because the study game purposely varied where the squares appeared on the left or right side of the visual field, the data also added more evidence for a discovery Miller and colleagues first reported back in 2009: Visual working memory is distinct for each side of the visual field. People have independent capacities on their left and their right, research has confirmed.

The Miller Lab is now working on a new study that tracks how the three regions interact when working memory information must be shared across the visual field.

The insights Miller’s lab has produced into visual working memory led him to start the company SplitSage , which last month earned a patent for technology to measure people’s positional differences in visual working memory capacity. The company hopes to use insights from Miller’s research to optimize heads-up displays in cars and to develop diagnostic tests for disorders like dementia among other applications. Miller is the company’s chief scientist and Buschman is chair of the advisory board.

The more scientists learn about how working memory works, and more generally about how brain waves synchronize higher level cognitive functions, the more ways they may be able to apply that knowledge to help people, Miller said.

“If we can figure out what things rhythms are doing and how they are doing them and when they are doing them, we may be able to find a way to strengthen the rhythms when they need to be strengthened,” he said.

This article has been republished from materials provided by The Picower Institute for Learning and Memory. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference:
Dimitris A Pinotsis, Timothy J Buschman, Earl K Miller; Working Memory Load Modulates Neuronal Coupling, Cerebral Cortex, https://doi.org/10.1093/cercor/bhy065

https://www.technologynetworks.com/neuroscience/news/heavy-working-memory-load-sinks-brainwave-synch-299481?utm_campaign=Newsletter_TN_BreakingScienceNews&utm_source=hs_email&utm_medium=email&utm_content=61943552&_hsenc=p2ANqtz-9YXYfgZV0xyox9-5P2gNPpCxLjaaoa_RPBQqrpLSXU-va1pfx1t7Z-t-myuu0_NK28T90fFH7eTsE21icgPGmxbSMXfA&_hsmi=61943552

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by Robbie Gonzalez

THE SHAPE ON the screen appears only briefly—just long enough for the test subject to commit it to memory. At the same time, an electrical signal snakes past the bony perimeter of her skull, down through a warm layer of grey matter toward a batch of electrodes near the center of her brain. Zap zap zap they go, in a carefully orchestrated pattern of pulses. The picture disappears from the screen. A minute later, it reappears, this time beside a handful of other abstract images. The patient pauses, recognizes the shape, then points to it with her finger.

What she’s doing is remarkable, not for what she remembers, but for how well she remembers. On average, she and seven other test subjects perform 37 percent better at the memory game with the brain pulses than they do without—making them the first humans on Earth to experience the memory-boosting benefits of a tailored neural prosthesis.

If you want to get technical, the brain-booster in question is a “closed-loop hippocampal neural prosthesis.” Closed loop because the signals passing between each patient’s brain and the computer to which it’s attached are zipping back and forth in near-real-time. Hippocampal because those signals start and end inside the test subject’s hippocampus, a seahorse-shaped region of the brain critical to the formation of memories. “We’re looking at how the neurons in this region fire when memories are encoded and prepared for storage,” says Robert Hampson, a neuroscientist at Wake Forest Baptist Medical Center and lead author of the paper describing the experiment in the latest issue of the Journal of Neural Engineering.

By distinguishing the patterns associated with successfully encoded memories from unsuccessful ones, he and his colleagues have developed a system that improves test subjects’ performance on visual memory tasks. “What we’ve been able to do is identify what makes a correct pattern, what makes an error pattern, and use microvolt level electrical stimulations to strengthen the correct patterns. What that has resulted in is an improvement of memory recall in tests of episodic memory.” Translation: They’ve improved short-term memory by zapping patients’ brains with individualized patterns of electricity.

Today, their proof-of-concept prosthetic lives outside a patient’s head and connects to the brain via wires. But in the future, Hampson hopes, surgeons could implant a similar apparatus entirely within a person’s skull, like a neural pacemaker. It could augment all manner of brain functions—not just in victims of dementia and brain injury, but healthy individuals, as well.

If the possibility of a neuroprosthetic future strikes you as far-fetched, consider how far Hampson has come already. He’s been studying the formation of memories in the hippocampus since the 1980s. Then, about two decades ago, he connected with University of Southern California neural engineer Theodore Berger, who had been working on ways to model hippocampal activity mathematically. The two have been collaborating ever since. In the early aughts, they demonstrated the potential of a neuroprosthesis in slices of brain tissue. In 2011 they did it in live rats. A couple years later, they pulled it off in live monkeys. Now, at long last, they’ve done it in people.

“In one sense, that makes this prosthesis a culmination,” Hampson says. “But in another sense, it’s just the beginning. Human memory is such a complex process, and there is so much left to learn. We’re only at the edge of understanding it.”

To test their system in human subjects, the researchers recruited people with epilepsy; those patients already had electrodes implanted in their hippocampi to monitor for seizure-related electrical activity. By piggybacking on the diagnostic hardware, Hampson and his colleagues were able to record, and later deliver, electrical activity.

You see, the researchers weren’t just zapping their subjects’ brains willy nilly. They determined where and when to deliver stimulation by first recording activity in the hippocampus as each test subject performed the visual memory test described above. It’s an assessment of working memory—the short-term mental storage bin you use to stash, say, a two-factor authentication code, only to retrieve it seconds later.

All the while, electrodes were recording the brain’s activity, tracking the firing patterns in the hippocampus when the patient guessed right and wrong. From those patterns, Berger, together with USC biomedical engineer Dong Song, created a mathematical model that could predict how neurons in each subject’s hippocampus would fire during successful memory-formation. And if you can predict that activity, that means you can stimulate the brain to mimic that memory formation.

Stimulating the patients’ hippocampi had a similar effect on longer-term memory retention—like your ability to remember where you parked when you leave the grocery store. In a second test, Hampson’s team introduced a 30- to 60-minute delay between displaying an image and asking the subjects to pull it out of a lineup. On average, test subjects performed 35 percent better in the stimulated trials.

The effect came as a shock to the researchers. “We weren’t surprised to see improvement, because we’d had success in our preliminary animal studies. We were surprised by the amount of improvement,” Hampson says. “We could tell, as we were running the patients, that they were performing better. But we didn’t appreciate how much better until we went back and analyzed the results.”

The results have impressed other researchers, as well. “The loss of one’s memories and the ability to encode new memories is devastating—we are who we are because of the memories we have formed throughout our lifetimes,” Rob Malenka, a psychiatrist and neurologist at Stanford University who was unaffiliated with the study, said via email. In that light, he says, “this very exciting neural prosthetic approach, which borders on science fiction, has great potential value. (Malenka has expressed cautious optimism about neuroprosthetic research in the past, noting as recently as 2015 that the translation of the technology from animal to human subjects would constitute “a huge leap.”) However, he says, it’s important to be remain clear-headed. “This kind of approach is certainly worth pursuing with vigor but I think it will still be decades before this kind of approach will ever be used routinely in large numbers of patient populations.”

Then again, with enough support, it could happen sooner than that. Facebook is working on brain computer interfaces; so is Elon Musk. Berger himself briefly served as the chief science officer of Kernel, an ambitious neurotechnology startup led by entrepreneur Bryan Johnson. “Initially, I was very hopeful about working with Bryan,” Berger says now. “We were both excited about the possibility of the work, and he was willing to put in the kind of money that would be required to see it thrive.”

But the partnership crumbled, right in the middle of Kernel’s first clinical test. Berger declines to go into details, except to say that Johnson—either out of hubris or ignorance—wanted to move too fast. (Johnson declined to comment for this story.)

https://www.wired.com/story/hippocampal-neural-prosthetic?mbid=nl_040618_daily_list3_p1&CNDID=50678559


Illustration by Paweł Jońca

by Helen Thomson

In March 2015, Li-Huei Tsai set up a tiny disco for some of the mice in her laboratory. For an hour each day, she placed them in a box lit only by a flickering strobe. The mice — which had been engineered to produce plaques of the peptide amyloid-β in the brain, a hallmark of Alzheimer’s disease — crawled about curiously. When Tsai later dissected them, those that had been to the mini dance parties had significantly lower levels of plaque than mice that had spent the same time in the dark.

Tsai, a neuroscientist at Massachusetts Institute of Technology (MIT) in Cambridge, says she checked the result; then checked it again. “For the longest time, I didn’t believe it,” she says. Her team had managed to clear amyloid from part of the brain with a flickering light. The strobe was tuned to 40 hertz and was designed to manipulate the rodents’ brainwaves, triggering a host of biological effects that eliminated the plaque-forming proteins. Although promising findings in mouse models of Alzheimer’s disease have been notoriously difficult to replicate in humans, the experiment offered some tantalizing possibilities. “The result was so mind-boggling and so robust, it took a while for the idea to sink in, but we knew we needed to work out a way of trying out the same thing in humans,” Tsai says.

Scientists identified the waves of electrical activity that constantly ripple through the brain almost 100 years ago, but they have struggled to assign these oscillations a definitive role in behaviour or brain function. Studies have strongly linked brainwaves to memory consolidation during sleep, and implicated them in processing sensory inputs and even coordinating consciousness. Yet not everyone is convinced that brainwaves are all that meaningful. “Right now we really don’t know what they do,” says Michael Shadlen, a neuroscientist at Columbia University in New York City.

Now, a growing body of evidence, including Tsai’s findings, hint at a meaningful connection to neurological disorders such as Alzheimer’s and Parkinson’s diseases. The work offers the possibility of forestalling or even reversing the damage caused by such conditions without using a drug. More than two dozen clinical trials are aiming to modulate brainwaves in some way — some with flickering lights or rhythmic sounds, but most through the direct application of electrical currents to the brain or scalp. They aim to treat everything from insomnia to schizophrenia and premenstrual dysphoric disorder.

Tsai’s study was the first glimpse of a cellular response to brainwave manipulation. “Her results were a really big surprise,” says Walter Koroshetz, director of the US National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. “It’s a novel observation that would be really interesting to pursue.”


A powerful wave

Brainwaves were first noticed by German psychiatrist Hans Berger. In 1929, he published a paper describing the repeating waves of current he observed when he placed electrodes on people’s scalps. It was the world’s first electroencephalogram (EEG) recording — but nobody took much notice. Berger was a controversial figure who had spent much of his career trying to identify the physiological basis of psychic phenomena. It was only after his colleagues began to confirm the results several years later that Berger’s invention was recognized as a window into brain activity.

Neurons communicate using electrical impulses created by the flow of ions into and out of each cell. Although a single firing neuron cannot be picked up through the electrodes of an EEG, when a group of neurons fires again and again in synchrony, it shows up as oscillating electrical ripples that sweep through the brain.

Those of the highest frequency are gamma waves, which range from 25 to 140 hertz. People often show a lot of this kind of activity when they are at peak concentration. At the other end of the scale are delta waves, which have the lowest frequency — around 0.5 to 4 hertz. These tend to occur in deep sleep (see ‘Rhythms of the mind’).

At any point in time, one type of brainwave tends to dominate, although other bands are always present to some extent. Scientists have long wondered what purpose, if any, this hum of activity serves, and some clues have emerged over the past three decades. For instance, in 1994, discoveries in mice indicated that the distinct patterns of oscillatory activity during sleep mirrored those during a previous learning exercise. Scientists suggested that these waves could be helping to solidify memories.

Brainwaves also seem to influence conscious perception. Randolph Helfrich at the University of California, Berkeley, and his colleagues devised a way to enhance or reduce gamma oscillations of around 40 hertz using a non-invasive technique called transcranial alternating current stimulation (tACS). By tweaking these oscillations, they were able to influence whether a person perceived a video of moving dots as travelling vertically or horizontally.

The oscillations also provide a potential mechanism for how the brain creates a coherent experience from the chaotic symphony of stimuli hitting the senses at any one time, a puzzle known as the ‘binding problem’. By synchronizing the firing rates of neurons responding to the same event, brainwaves might ensure that the all of the relevant information relating to one object arrives at the correct area of the brain at exactly the right time. Coordinating these signals is the key to perception, says Robert Knight, a cognitive neuroscientist at the University of California, Berkeley, “You can’t just pray that they will self-organize.”


Healthy oscillations

But these oscillations can become disrupted in certain disorders. In Parkinson’s disease, for example, the brain generally starts to show an increase in beta waves in the motor regions as body movement becomes impaired. In a healthy brain, beta waves are suppressed just before a body movement. But in Parkinson’s disease, neurons seem to get stuck in a synchronized pattern of activity. This leads to rigidity and movement difficulties. Peter Brown, who studies Parkinson’s disease at the University of Oxford, UK, says that current treatments for the symptoms of the disease — deep-brain stimulation and the drug levodopa — might work by reducing beta waves.

People with Alzheimer’s disease show a reduction in gamma oscillations5. So Tsai and others wondered whether gamma-wave activity could be restored, and whether this would have any effect on the disease.

They started by using optogenetics, in which brain cells are engineered to respond directly to a flash of light. In 2009, Tsai’s team, in collaboration with Christopher Moore, also at MIT at the time, demonstrated for the first time that it is possible to use the technique to drive gamma oscillations in a specific part of the mouse brain6.

Tsai and her colleagues subsequently found that tinkering with the oscillations sets in motion a host of biological events. It initiates changes in gene expression that cause microglia — immune cells in the brain — to change shape. The cells essentially go into scavenger mode, enabling them to better dispose of harmful clutter in the brain, such as amyloid-β. Koroshetz says that the link to neuroimmunity is new and striking. “The role of immune cells like microglia in the brain is incredibly important and poorly understood, and is one of the hottest areas for research now,” he says.

If the technique was to have any therapeutic relevance, however, Tsai and her colleagues had to find a less-invasive way of manipulating brainwaves. Flashing lights at specific frequencies has been shown to influence oscillations in some parts of the brain, so the researchers turned to strobe lights. They started by exposing young mice with a propensity for amyloid build-up to flickering LED lights for one hour. This created a drop in free-floating amyloid, but it was temporary, lasting less than 24 hours, and restricted to the visual cortex.

To achieve a longer-lasting effect on animals with amyloid plaques, they repeated the experiment for an hour a day over the course of a week, this time using older mice in which plaques had begun to form. Twenty-four hours after the end of the experiment, these animals showed a 67% reduction in plaque in the visual cortex compared with controls. The team also found that the technique reduced tau protein, another hallmark of Alzheimer’s disease.

Alzheimer’s plaques tend to have their earliest negative impacts on the hippocampus, however, not the visual cortex. To elicit oscillations where they are needed, Tsai and her colleagues are investigating other techniques. Playing rodents a 40-hertz noise, for example, seems to cause a decrease in amyloid in the hippocampus — perhaps because the hippo-campus sits closer to the auditory cortex than to the visual cortex.

Tsai and her colleague Ed Boyden, a neuro-scientist at MIT, have now formed a company, Cognito Therapeutics in Cambridge, to test similar treatments in humans. Last year, they started a safety trial, which involves testing a flickering light device, worn like a pair of glasses, on 12 people with Alzheimer’s.

Caveats abound. The mouse model of Alzheimer’s disease is not a perfect reflection of the disorder, and many therapies that have shown promise in rodents have failed in humans. “I used to tell people — if you’re going to get Alzheimer’s, first become a mouse,” says Thomas Insel, a neuroscientist and psychiatrist who led the US National Institute of Mental Health in Bethesda, Maryland, from 2002 until 2015.

Others are also looking to test how manipulating brainwaves might help people with Alzheimer’s disease. “We thought Tsai’s study was outstanding,” says Emiliano Santarnecchi at Harvard Medical School in Boston, Massachusetts. His team had already been using tACS to stimulate the brain, and he wondered whether it might elicit stronger effects than a flashing strobe. “This kind of stimulation can target areas of the brain more specifically than sensory stimulation can — after seeing Tsai’s results, it was a no-brainer that we should try it in Alzheimer’s patients.”

His team has begun an early clinical trial in which ten people with Alzheimer’s disease receive tACS for one hour daily for two weeks. A second trial, in collaboration with Boyden and Tsai, will look for signals of activated microglia and levels of tau protein. Results are expected from both trials by the end of the year.

Knight says that Tsai’s animal studies clearly show that oscillations have an effect on cellular metabolism — but whether the same effect will be seen in humans is another matter. “In the end, it’s data that will win out,” he says.

The studies may reveal risks, too. Gamma oscillations are the type most likely to induce seizures in people with photosensitive epilepsy, says Dora Hermes, a neuroscientist at Stanford University in California. She recalls a famous episode of a Japanese cartoon that featured flickering red and blue lights, which induced seizures in some viewers. “So many people watched that episode that there were almost 700 extra visits to the emergency department that day.”

A brain boost

Nevertheless, there is clearly a growing excitement around treating neurological diseases using neuromodulation, rather than pharmaceuticals. “There’s pretty good evidence that by changing neural-circuit activity we can get improvements in Parkinson’s, chronic pain, obsessive–compulsive disorder and depression,” says Insel. This is important, he says, because so far, pharmaceutical treatments for neurological disease have suffered from a lack of specificity. Koroshetz adds that funding institutes are eager for treatments that are innovative, non-invasive and quickly translatable to people.

Since publishing their mouse paper, Boyden says, he has had a deluge of requests from researchers wanting to use the same technique to treat other conditions. But there are a lot of details to work out. “We need to figure out what is the most effective, non-invasive way of manipulating oscillations in different parts of the brain,” he says. “Perhaps it is using light, but maybe it’s a smart pillow or a headband that could target these oscillations using electricity or sound.” One of the simplest methods that scientists have found is neurofeedback, which has shown some success in treating a range of conditions, including anxiety, depression and attention-deficit hyperactivity disorder. People who use this technique are taught to control their brainwaves by measuring them with an EEG and getting feedback in the form of visual or audio cues.

Phyllis Zee, a neurologist at Northwestern University in Chicago, Illinois, and her colleagues delivered pulses of ‘pink noise’ — audio frequencies that together sound a bit like a waterfall — to healthy older adults while they slept. They were particularly interested in eliciting the delta oscillations that characterize deep sleep. This aspect of sleep decreases with age, and is associated with a decreased ability to consolidate memories.

So far, her team has found that stimulation increased the amplitude of the slow waves, and was associated with a 25–30% improvement in recall of word pairs learnt the night before, compared with a fake treatment7. Her team is midway through a clinical trial to see whether longer-term acoustic stimulation might help people with mild cognitive impairment.

Although relatively safe, these kinds of technologies do have limitations. Neurofeedback is easy to learn, for instance, but it can take time to have an effect, and the results are often short-lived. In experiments that use magnetic or acoustic stimulation, it is difficult to know precisely what area of the brain is being affected. “The field of external brain stimulation is a little weak at the moment,” says Knight. Many approaches, he says, are open loop, meaning that they don’t track the effect of the modulation using an EEG. Closed loop, he says, would be more practical. Some experiments, such as Zee’s and those involving neuro-feedback, already do this. “I think the field is turning a corner,” Knight says. “It’s attracting some serious research.”

In addition to potentially leading to treatments, these studies could break open the field of neural oscillations in general, helping to link them more firmly to behaviour and how the brain works as a whole.

Shadlen says he is open to the idea that oscillations play a part in human behaviour and consciousness. But for now, he remains unconvinced that they are directly responsible for these phenomena — referring to the many roles people ascribe to them as “magical incantations”. He says he fully accepts that these brain rhythms are signatures of important brain processes, “but to posit the idea that synchronous spikes of activity are meaningful, that by suddenly wiggling inputs at a specific frequency, it suddenly elevates activity onto our conscious awareness? That requires more explanation.”

Whatever their role, Tsai mostly wants to discipline brainwaves and harness them against disease. Cognito Therapeutics has just received approval for a second, larger trial, which will look at whether the therapy has any effect on Alzheimer’s disease symptoms. Meanwhile, Tsai’s team is focusing on understanding more about the downstream biological effects and how to better target the hippocampus with non-invasive technologies.

For Tsai, the work is personal. Her grandmother, who raised her, was affected by dementia. “Her confused face made a deep imprint in my mind,” Tsai says. “This is the biggest challenge of our lifetime, and I will give it all I have.”

https://www.nature.com/articles/d41586-018-02391-6

Low-current electrical pulses delivered to a specific brain area during learning improved recollection of distinct memories, according to a study published online in eLife.

Researchers at the University of California, Los Angeles (UCLA) believe electrical stimulation offers hope for the treatment of memory disorders, such as Alzheimer’s disease.

The study involved 13 patients with epilepsy who had ultrafine wires implanted in their brains to pinpoint the origin of seizures. During a person-recognition task, researchers monitored the wires to record neuronal activity as memories were formed, and then sent a specific pattern of quick pulses to the entorhinal area of the brain, an area critical to learning and memory.
In 8 of 9 patients who received electrical pulses to the right side of the entorhinal area, the ability to recognize specific faces and disregard similar-looking ones improved significantly. However, the 4 patients who received electrical stimulation on the left side of the brain area showed no improvement in recall.

By using the ultrafine wires, researchers were able to precisely target the stimulation while using a voltage that was one-tenth to one-fifth of the strength used in previous studies.

“These results suggest that microstimulation with physiologic level currents—a radical departure from commonly used deep brain stimulation protocols—is sufficient to modulate human behavior,” researchers wrote.

The findings also point to the importance of stimulating the right entorhinal region to promote improved memory recollection.

—Jolynn Tumolo

References

Titiz AS, Hill MRH, Mankin EA, et al. Theta-burst microstimulation in the human entorhinal area improves memory specificity. eLife. 2017 October 24.

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by Linda Rodriguez McRobbie

If you ask Jill Price to remember any day of her life, she can come up with an answer in a heartbeat. What was she doing on 29 August 1980? “It was a Friday, I went to Palm Springs with my friends, twins, Nina and Michelle, and their family for Labour Day weekend,” she says. “And before we went to Palm Springs, we went to get them bikini waxes. They were screaming through the whole thing.” Price was 14 years and eight months old.

What about the third time she drove a car? “The third time I drove a car was January 10 1981. Saturday. Teen Auto. That’s where we used to get our driving lessons from.” She was 15 years and two weeks old.

The first time she heard the Rick Springfield song Jessie’s Girl? “March 7 1981.” She was driving in a car with her mother, who was yelling at her. She was 16 years and two months old.

Price was born on 30 December 1965 in New York City. Her first clear memories start from around the age of 18 months. Back then, she lived with her parents in an apartment across the street from Roosevelt Hospital in Midtown Manhattan. She remembers the screaming ambulances and traffic, how she used to love climbing on the living room couch and staring out of the window down 9th Avenue.

When she was five years and three months old, her family – her father, a talent agent with William Morris who counted Ray Charles among his clients; her mother, a former variety show dancer, and her baby brother – moved to South Orange, New Jersey. They lived in a three-storey, red brick colonial house with a big backyard and huge trees, the kind of place people left the city for. Jill loved it.

When she was seven years old, her father was offered a job with Columbia Pictures Television in Los Angeles. He spent a year commuting back and forth from California to New Jersey, until he and her mother decided to move the family out there in the spring of 1974. By 1 July 1974, when Jill was eight and a half, they were living in a rented house in Los Angeles. That was the day, she says, her “brain snapped”.

She had always had a talent for remembering. She had also always dreaded change. Knowing that after they left New Jersey, nothing could ever be the same, Price tried to commit to memory the world she was being ripped away from. She made lists, took pictures, kept every artefact, every passed note and ticket stub. If this was a conscious effort to train her memory, it worked, perhaps better than she ever imagined.

Price was the first person ever to be diagnosed with what is now known as highly superior autobiographical memory, or HSAM, a condition she shares with around 60 other known people. She can remember most of the days of her life as clearly as the rest of us remember the recent past, with a mixture of broad strokes and sharp detail. Now 51, Price remembers the day of the week for every date since 1980; she remembers what she was doing, who she was with, where she was on each of these days. She can actively recall a memory of 20 years ago as easily as a memory of two days ago, but her memories are also triggered involuntarily.

It is, she says, like living with a split screen: on the left side is the present, on the right is a constantly rolling reel of memories, each one sparked by the appearance of present-day stimuli. With so many memories always at the ready, Price says, it can be maddening: virtually anything she sees or hears can be a potential trigger.

Before Price, HSAM was a completely unknown condition. So what about the day she sent an email to a Dr James McGaugh at University of California, Irvine? That was 8 June 2000, a Thursday. Price was 34 years and five months old.

Dr James McGaugh remembers that day too. At the time, he was director of UC Irvine’s Center for the Neurobiology of Learning and Memory, the research institute that he founded in 1983. In her email, Jill Price said that she had a problem with her memory. McGaugh responded almost immediately, explaining that he worked at a research institute and not a clinic, and that he’d be happy to direct her to somewhere she could find help.

Price’s reply was swift and unexpected. “Whenever I see a date flash on the television (or anywhere else for that matter), I automatically go back to that day and remember where I was, what I was doing, what day it fell on and on and on and on and on. It is non-stop, uncontrollable and totally exhausting … Most have called it a gift but I call it a burden. I run my entire life through my head every day and it drives me crazy!!!”

McGaugh was a little wary, but he was intrigued. He invited her to his office to talk.

On the morning of Saturday, 24 June 2000, Price woke up “so, so, so excited”. She watched Apple’s Way, an obscure, short-lived 1970s series being re-run on TV, and felt, for the first time in ages, relaxed. She asked her father whether she should take all of the diaries that she had been keeping since Monday, 24 August 1981. No, he said, don’t take them all – you’ll freak him out. She packed a bag with six years’ worth, stowed them in the boot of her car, and set off to meet McGaugh.

She drove the hour south from her home in Encino, California, where she lived with her parents, and met McGaugh outside the Qureshey Research Building on the UC Irvine campus. It was a cloudy day, unusual for southern California. As they walked up to his second-floor office, she was still excited.

For Christmas the previous year, McGaugh had received a massive coffee-table book called 20th Century Day by Day, featuring photographs and brief accounts of the biggest news stories of the past 100 years. To test Price’s memory, he and his assistant used the book to come up with questions that someone with amazing powers of recall might plausibly be able to answer, beginning around 1974, when Price said her ability to remember really started.

Sitting across from Price, McGaugh asked, “When did the Iranian hostage crisis begin?”

After a brief pause, she answered, “4 November 1979.”

“No, that’s not right,” he said. “It was 5 November.”

“It was 4 November,” she said.

He checked another source: Price was right; the book was wrong.

The rest of Price’s responses came just as quickly, confidently, and for the most part, correctly. What day did the Los Angeles police beat taxi driver Rodney King? Sunday, 3 March 1991. What happened on 16 August 1977? Elvis Presley died in his Graceland bathroom. It was a Tuesday. When did Bing Crosby die? Friday, 14 October 1977, on a golf course in Spain. Price heard it on the radio in the car while her mother drove her to soccer practice.

McGaugh had been studying memory and learning for decades and he had never seen or heard of anything like this. After they had eaten lunch, Price remembers saying goodbye to McGaugh as he stood on the curb outside the restaurant, “literally scratching his head”.

Driving back, Price felt a little deflated. “I came home and I was kind of annoyed, and my dad said, ‘What did you expect, you’d get an answer?’” she recalled. “And I’m like, ‘Yeah! And I thought I’d get a pill for it, too!’”

McGaugh is a big deal in memory research. His office at UC Irvine is situated across a courtyard from another building, McGaugh Hall, named in his honour. He has written more than 550 papers and books, many on his specialist subject of how we form long-term memories. In 2015 he received a Grawemeyer award, a significant recognition in the crowded field of psychology that comes with a $100,000 prize, for his contribution to understanding memory and emotion. The small plaque sits on a shelf on his desk. Thumbtacked to a bulletin board next to his computer monitor is a colour photograph of McGaugh – trim grey beard, square glasses, academic robes – standing behind President Barack Obama during UCI’s graduation ceremony in 2014. The funny thing about that picture, McGaugh told me when I visited him last autumn, is that the photographer was actually trying to get a picture of him, not the president, for an article in the Los Angeles Times about McGaugh’s 50th anniversary at the university. “This is the absolute truth, but no one will believe it!” he said, chuckling.

McGaugh, who is now 85 and closing in on retirement, first began studying memory in the 1950s. By the time Price contacted him, his research focused on showing that the more emotionally provocative an experience, the more likely the neurobiological systems involved in making memory will ensure that you remember it. When something even slightly stimulating happens, positive or negative, it causes the release of adrenal stress hormones, which in turn activate the amygdala. The amygdala then projects to other brain regions that the thing that has just happened is important and needs to be remembered. It is through this system, McGaugh explained, that the strength of our memories is controlled.

McGaugh had spent his professional career studying strongly formed memories, and Price seemed to have the strongest memories he had ever encountered. McGaugh’s earlier work had changed how we understand the mechanisms of memory, and his interest in Price was about more than just understanding her extraordinary abilities of recollection. He hoped that her unique condition could teach us something new about how we make and store memories. “The big pay-off on this,” he said, “is understanding how memory works.”

Still, he started from a position of scepticism. “In interrogating her, I started with the scientific assumption that she couldn’t do it,” he told me. And even though Price showed that she could, repeatedly, McGaugh was still unmoved. “Yeah, it got my attention, but I didn’t say, ‘Wow.’ We had to do a lot more. So we did a lot more.” (In Price’s recollection, however, her ability to remember “really freaked Dr McGaugh out.”)

After his first meeting with Price, McGaugh assembled a team to determine the depth and breadth of her memory. Elizabeth Parker, a neuropsychologist, mapped Price’s ability to learn and remember, and Larry Cahill, a neurobiologist, helped to analyse the results. Over the next five years, Price was given a battery of standardised memory, IQ and learning tests, as well as a series of specially devised ones. For example, they asked Price, who is Jewish, to write down the date of every Easter from 1980 to 2003 – she got only one wrong and in that case, she was off by only two days. Price was also able to say what she had done on those days. When the researchers asked her to do the same exercise again two years later, she not only corrected the date she had got wrong, but also gave the same answers for the personal details (a sample of those details: 17 April 1987 – “vomit up carrots”; 12 April 1998: “house smells like ham”).

Confirming whether or not autobiographical memories are accurate is usually a tricky job but, McGaugh said, “fortunately, she kept a diary”. Price had begun recording the details of her life in earnest on 24 August 1980, during a high-school romance she wanted to remember. She would make at least one, usually more, entry each day, comprising of short references to the most salient details of the day. Her journals were kept on calendars, on typing paper held together with binder clips, in notebooks, on index cards, even scrawled on the wallpaper in her childhood bedroom.

For Price, writing down her memories meant that they were “real”, part of a permanent historical record independent of herself. (When she dies, she told me, she wants her journals buried with her, or blown up in the desert.) They also functioned as a way to pin down the swirling mess in her head, to organise her thoughts. Price says she does not re-read her journals, and given the random dates the researchers threw at her, there is no reason to assume she could have prepared for their questions. The UCI researchers cross-referenced what she said she did with what was written in her diary; in some cases, they were also able to verify memories with her mother.

Over time, it became clear that Price’s autobiographical memory was potentially unprecedented. But when it came to remembering details that did not relate to her personally, Price proved no better than average. She recalled the date the Iran hostage crisis began because, as a self-described “news junkie”, she had made that detail part of her personal narrative of the day it happened. School, she says, was “torture” for her – she couldn’t remember facts and figures – but she’s unbelievably good at trivia about television of the 60s and 70s, her nostalgia years. Other details, if they didn’t relate to her or her interests, were forgotten: once, she was asked to close her eyes and recall what her two interviewers, who she’d spent several hours with that day, were wearing – she couldn’t. When asked to look at a bank of random numbers and memorise their order in a given period of time, she laughed and said it was impossible. Price’s memory is as selective as yours or mine, storing the things that she finds important – she is just a good deal better at retaining and retrieving those memories.

There was very little scientific literature about superior forms of memory, and none about a memory like Jill Price’s. Much of what did exist was about people who had the ability to memorise pi out to 22,514 decimal places or remember the order of a randomly shuffled deck of cards. The scientific consensus about these abilities was that they were the result of practice and acquired skill – strategy, rather than innate ability. Other people who are able to name the day of the week for any given date are also able to do it for dates outside of their lifetimes, and they tend to be autistic. Price can’t and is not. There was no one – as far as the UCI team could find – who had ever exhibited anything like Price’s automatic ability to recall her personal memories.

On 13 August 2003, three years after she first came to Irvine, McGaugh, Parker, and Cahill presented their initial findings on Jill Price’s memory to the UCI medical community in a large open forum. Price was invited to exhibit her memory, to show how she could “see” dates and memories in her head, and to explain how she conceives time: for her, each year is like a circle, with January in the 11 o’clock position, and the months progressing in an anti-clockwise motion. She was nervous about speaking in front of a large audience, especially of doctors – she has a phobia of doctors, she says – but it was the beginning of her seeing a “bigger picture” reason for her years of suffering: scientific progress.

Two years later, the UCI researchers asked Price to read a draft of the paper they had written about her before they submitted it. In it, they described Price as both the “warden and prisoner” of her memories. “I thought, God, if I didn’t know better, it sounds like this person has brain damage or something,” she said of “AJ”, the pseudonym they used for her. “I cried. I wept while I read it. Someone had finally heard me. Because I’ve spent my whole life screaming at the top of my lungs and nobody has heard anything.”

“A Case of Unusual Autobiographical Remembering” was published by the neuropsychology journal Neurocase in February 2006. “We made the mistake of calling it ‘hyperthymesia’” – from the Greek thymesis, remembering – “which was a terrible idea, because when you name it in that way, it sounds as if you know what it is,” McGaugh said. In truth, all they had, in Price, was a data point of one, a lot of description, and no clear understanding of the mechanisms behind her memory. What they were about to get, however, was more people like Jill Price.

Price remembers 12 March 2006 as a very important day. “That was the last day that my life was my own,” she told me. The following morning, the first newspaper article about the discovery of “hyperthymesia” came out in the Orange County Register. By that afternoon, McGaugh’s assistant had already been contacted by five more media outlets who wanted to interview Price. A month later, the university was getting so many calls about Price that it asked her to hire a publicist to handle all the requests. (Price, who was still known to the public only as AJ, invented a publicist and fielded all the queries herself. “I had control over what was happening. For a year, nobody knew they were talking to me,” she says, “it was really quite hysterical.”)

Almost immediately, emails also began to trickle in to McGaugh’s office from people who believed that they or someone they knew had the same condition. One email even pointed out that the scientists at UC Irvine were not the first to find someone with a memory like this – an 1871 article in the Journal of Speculative Philosophy described the curious case of Daniel McCartney, then a 54-year-old blind man living in Ohio who could remember the day of the week, the weather, what he was doing, and where he was for any date back to 1 January 1827, when he was nine years and four months old.

http://www.jstor.org/stable/25665736?seq=1#page_scan_tab_contents

Dozens of people contacted McGaugh’s lab, where his assistant handled the first round of vetting, putting potential candidates through the same public events date test that McGaugh had initially given Price. The second person verified as having the condition was Brad Williams, a radio announcer in Wisconsin whose brother contacted McGaugh in 2007 after coming across an article about the UCI research. The third was Rick Baron, whose sister had read about “AJ” in online reports.

The fourth was Bob Petrella, a standup comic turned writer and TV producer for reality programmes such as The Deadliest Catch. Petrella had known since adolescence that his memory was different to other people’s, but he never thought it was all that unusual. “I just thought it was like being a redhead or being left-handed,” he told me when we met in Los Angeles in October.

Petrella sought out the UCI team after a friend suggested, on 19 June 2007, that he should learn the science behind his memory. He was referred to Elizabeth Parker, the neuropsychologist who had co-written the original paper on hyperthymesia. They met several times. After testing him, she confirmed that yes, Petrella had it, and sent him to McGaugh for further study. He met McGaugh and Cahill for the first time over lunch on 28 June 2008 (a “beautiful day”), where McGaugh quizzed him on dates just as he had done with Jill Price.

For the scientists, the research was exciting, but there was a concern as well, that it might all be a waste of time: given that such a tiny number of people with the condition had been identified, what could they definitively say about the condition? And what could this unique group reveal about memory? The only way to move forward was to continue testing the existing subjects and hope for more. By 2012, researchers had only identified six confirmed cases of what had been renamed highly superior autobiographical memory, or HSAM. (“Hyperthymesia”, McGaugh said, sounded “like a venereal disease”.) That’s when the news magazine programme 60 Minutes came calling.

In August 2010, 60 Minutes interviewed the “memory wizards” Bob Petrella, Brad Williams, Rick Baron, Louise Owen, and the actress Marilu Henner, best known for her role on the 1970s sitcom Taxi, for a segment entitled “Endless Memory”. (Price was not involved; by this time, she was no longer anonymous, having published a memoir in 2008, but she had begun to sour on media appearances, which she felt reduced her condition to a “sideshow”, and she has never met any of the other people with the condition.)

It was the first time that the HSAM subjects had met anyone like themselves and, watching the show today, the shock and delight in their mutual recognition is evident. When they first met on camera, there was a lot of hugging. Later, when quizzed on the date of a San Francisco earthquake, they give the answer almost in unison, some of them grinning. The programme aired on 19 December 2010 – a Sunday night – and was seen by nearly 19 million people.

After the programme was over, McGaugh said: “I turned on my computer and I had over 600 emails.” Most were from people who believed they or someone they knew had HSAM. McGaugh spent the week between Christmas and New Year’s Day responding to the emails. Graduate and undergraduate students were pressed into service to staff a phone bank, using the public events quiz to screen callers. Most were rejected, but a small group were invited to UCI for more testing. It is a measure of just how rare HSAM is that by 2011, even after millions of people had heard about it, researchers had identified only 22 people with the condition.

In May 2012, the journal Neurobiology of Learning and Memory published a follow-up study by UCI neuroscience graduate student Aurora LePort and neurobiologist Dr Craig Stark, then the director of the UCI Center for the Neurobiology of Learning and Memory. It was now nearly 12 years since Price first reached out to McGaugh, but researchers were only fractionally closer to finding the answer she was looking for.

In order to figure out how HSAM worked, researchers first needed to understand what it was and was not. LePort’s paper, the second to be published on the subject, established that Price and the 10 others in the study were not just high achievers on a spectrum of “good” to “bad” memory, they were in a separate, outlying class by themselves. The HSAM subjects turned out to be far better than people with average memories at recalling long-past autobiographical data; in memories that could be verified, they were correct 87% of the time. And the paper was able to offer some clues as to why they could do what they do.

For example, most of the HSAM subjects described mental systems that would seemingly improve retrieval, sorting memories chronologically or categorically (as in, every 15 April as far back as they could remember). This date-based structure seemed to help them organise their memories, as though they were tagging them for easy reference. Significantly, research shows that people with average memories are bad at temporally placing remembered events – we don’t have a sense of whether that thing happened two weeks ago or two months ago. (It is important to note here, as LePort, McGaugh, and Stark all did, that their research is limited by what they, as investigators, can verify as a real memory. Dates are the easiest and perhaps surest way to do that. “Everything we do is built around the ability to date. So are there people who have strong autobiographical memory who simply don’t bother to date them?” McGaugh said. “We’re missing them.”)

All of the HSAM subjects reported that they enjoyed replaying their memories in their minds, challenging themselves to remember days and events. When Jill Price is blow-drying her hair, she said, she flips through her memories of, say, every 4 October she can remember. “I’ll just do like the last 40 years in my head, the last 42 years in my head,” she said. “And then I’ll turn to an imaginary person in my head and say, ‘Now you do that. Go.’” When Bob Petrella is stuck in traffic, he scrolls through memories of that date, catalogues the best Saturdays in June he’s ever had, or tries to remember every day from 2002.

The researchers also noted that most of the HSAM subjects exhibited obsessive behaviours. Rick Baron used to keep every banknote in alphabetical order by the name of city of the Federal Reserve Bank from which it was issued. Price has a storage space jammed with neatly organised collection of personal artefacts that she couldn’t let go of – dolls and toys, dozens of Beanie Babies, tapes of songs she recorded off the radio. Bob Petrella used to clean his groceries with an antibacterial wipe when he got home from the grocery store. “There was a nice positive correlation there, showing that the better their memory, the more OCD they were,” LePort said, adding that it makes sense: if subjects are exhibiting obsessive behaviours generally, then they might also be obsessively recalling their memories, rehearsing and therefore retrenching them, making them stronger. Every time they access that memory, it is easier because they have done it before – repetition is one of the surest ways to memorise information.

There were also neuro-physical differences between HSAM subjects and people with average memories. Examination of their brain scans showed that HSAM subjects exhibited structural differences in areas of the brain associated with autobiographical memory creation: increases in the parahippocampal gyrus, for example – an area that some studies show is engaged during the recollection of emotional memories – and increases in the uncinate fascicle, the bridge between the frontal and temporal cortices that transmits information and is involved in episodic memory retention.

But none of these findings fully explains what enables people with HSAM to remember so much. After all, correlation is not causation. Whether their mental organisational systems helped the HSAM subjects to retain memories or whether they needed to develop elaborate systems because they could retain all those memories is unclear. Plenty of people rehearse their memories and don’t have HSAM, and plenty of people with OCD don’t have incredible recall of their autobiographical memories.

Even the structural differences in the brain, though significant, do not provide a satisfying explanation for why and how HSAM works. How we use our brain can change it physically – for example, a 2011 study of London taxi drivers found that the exercise of navigating the city’s dense streets led to an increase in grey matter volume in the mid-posterior hippocampus and an accompanying decrease in volume of the anterior hippocampus. Whether the differences in the HSAM brain is the cause of their memory or, as in the London taxi drivers, the result of it, or a combination of both, remains unclear. “Pulling that apart, in science, isn’t going to be easy. Especially when your population is so rare,” said Stark.

For both Price and Petrella, there is a specific point in their lives that they feel triggered their ability to remember things with extraordinary clarity. For Petrella, it was when he was seven years old and playing a deliriously fun game in his backyard with a childhood friend. The next day, Petrella invited his friend over to play it again, but they only played for a few minutes before getting bored. Petrella realised then that nothing ever stays the same and that it was important that he remember things before they changed. For Price, it was her family’s traumatic move to the west coast. In each case, Price and Petrella say they already had strong memories before this decisive moment, but after it, their ability to remember was transformed.

When I asked McGaugh what he thought of these backstory narratives, he was cautious. “How much of what they say is their own attempt at explanation for what exists as opposed to what really happened?” he asked. But Craig Stark is interested in those stories. He suggested that someone who feels anxiety about losing memories, the way Price and Petrella did, might be compelled to retain them, and therefore might think about them a lot.

Despite their amazing recall, however, there is one way that HSAM subjects are just like everyone else – they are just as prone to memory “distortions”, the editing, assumptions, conflation of time, and other discrepancies that are part and parcel of making memories.

In a study published in 2013, Dr Lawrence Patihis, a memory researcher at the University of Southern Mississippi working with scientists at UCI, asked 20 HSAM subjects and 38 people with standard memories to participate in a series of tests designed to assess their susceptibility to false memories. HSAM subjects were equally likely as the control group to claim words that had not appeared on a list had appeared, they showed a higher overall propensity to form false memories of a photographic slideshow, and they were equally likely to mistakenly report that they had seen non-existent video footage of the United 93 plane crash on 9/11.

The findings suggest that no one, not even a “memory wizard”, is immune to the reconstructive mechanisms that enable memory distortions. When people with average memory recall an experience, it is formed not only by what they think happened and how they felt at the time, but by what they know and feel now. “We’re pulling together everything in the present to come up with an approximation of the past, and that’s the same with HSAM people,” Patihis said. The findings were not popular with some of the HSAM subjects because, as Stark, a co-author on the paper, pointed out, having accurate memories is central to their identities.

But the findings square with two other important ideas. First, the initial process of encoding memories – that is, when the brain makes an experience into a memory, translating elements of that experience into a network of neurons and synaptic connections – seems no different for people with HSAM than for the rest of us.

In a study published in 2016, LePort and the other researchers tested the quality and quantity of autobiographical memories of HSAM and control groups at one week, one month, one year, and 10 years. At one week, both groups were the same in terms of the quality and quantity of information they recalled. After that first week, however, the controls’ powers of recall dropped off significantly, while HSAM people continued to be able to remember seemingly into perpetuity, with a much shallower forgetting curve. The evidence suggests that HSAM subjects form memories in much the same way as those of us with normal memories: like us, they make stronger memories of emotionally arousing experiences, and like us, they are prone to the same distortions in reconstruction.

The second idea is that however good they are at mentally representing and organising their memories, HSAM people don’t seem to be pulling up that information via a novel retrieval system. “It’s the same mechanism, it’s just better,” Stark, whose lab is now running most of the HSAM research, explained. This also implies that the thing HSAM people are doing differently to the rest of us happens somewhere in between the encoding of a memory and its retrieval – in the space where consolidation into a long-term memory takes place.

Testing that hypothesis is fairly straightforward: get HSAMs and controls into a functional MRI and ask them both to recall memories from about a week earlier, the time frame that both groups are performing at about the same level. “Are we thinking about it and reliving it in a different way?” said Stark. But that research is not happening – in part because of a lack of funding. HSAM is fascinating, but funding science for science’s sake is not popular in the US right now. Grant-giving institutions want to know what studying HSAM can do for us.

In 1953, 27-year-old Henry Molaison of Hartford, Connecticut, underwent a desperate surgery to cure his severe epilepsy. Drilling several holes in his head, surgeons performed a “bilateral medial temporal lobe resection”, essentially sucking away part of his hippocampus and much of his amygdala. The surgery worked – Molaison suffered fewer seizures – but it also left him unable to form new memories. His memories from before the surgery were intact, and he was able to learn new motor skills, but he was never able to recognise the researcher who worked with him for decades, whom he saw almost every day.

Molaison, who was known in medical journals as “HM” for the rest of his life, profoundly changed our scientific understanding of memory by showing that we don’t have a single, unified “memory system”. Instead, McGaugh explained, “We have different memory systems in the brain that handle different kinds of information for different periods of time.”

Understanding HSAM, he says, may lead to a similar revelation about the nature of memory. “That’s what is of interest,” he told me. “It’s not that HSAM is interesting, it’s that memory is interesting.”

Price and Petrella said that they hoped that studying their memories could aid research that would find a cure for the thing that surveys in Britain and America show people are most terrified of: dementia. Price, with characteristic directness, said: “I expect them to find a cure for Alzheimer’s. I told Dr McGaugh, ‘This is now your turn, go. Do what you got to do … No pressure, but just find a cure for Alzheimer’s.’”

In all likelihood, studying HSAM will not lead directly to a cure for Alzheimer’s or dementia. It is still unclear whether HSAM will turn out to be a fascinating curiosity, or a key that unlocks the deepest mysteries about how memory works. At the very least, Dr Dorthe Berntsen, founder of Aarhus University’s Center on Autobiographical Memory Research, told me, it shows the extraordinary potential of autobiographical memory. “Could I, as a non-HSAM person, have memory from each day in my life stored, but I just can’t get to it? Is that a retrieval problem or is it a storage and retention problem? Potentially, it can be very important, because it asks these new questions, it shows that we may have to revise how we have thought about our ability to remember the past.”

Every memory researcher I have ever spoken to describes our memories as the things that define us; they are us. There is a reason that people are more afraid of dementia than cancer. When someone you love dies, you fear the day you will forget how they laughed or the sound of their voice, because you will. It hurts to think of all the wonderful, thrilling, important, terrible, devastating things we’ve forgotten. But people with HSAM do remember. Besides the scientific questions HSAM raises, then, there is a different kind of question: would you want a memory like that, if you could have it?

“We call it forgetting but on the other hand, simple storage of information is stupid, it’s just data hoarding. What’s the point? You need to extract something useful from it, then we call it knowledge or wisdom,” Stark told me. “Memory is not about looking backwards, that is not why we have it. It’s there so that your past experiences will make you more adaptive in the here and now and in the future.” But when LePort asked her HSAM subjects in the 2012 study whether they considered their hoard of memories a burden, most said they did not.

Jill Price is not representative of everyone with HSAM, but she is the first data point in this small population. And Price wrote to McGaugh on Thursday 8 June, 2000, because she had a problem. “Everyone has those forks in the road, ‘If I had just done this and gone here, and nah nah nah,’ everyone has those,” she told me. “Except everyone doesn’t remember every single one of them.” Her memory is a map of regrets, other lives she could have lived. “I do this a lot: what would be, what would have been, or what would be today,” she said.

Price is now a freelance script supervisor for film and TV. She lives in an immaculate apartment in Encino, California with her parents, with whom she has lived for much of her adult life. She has a habit of looking off to the right, to the side of the split screen where her memories are, when we talk. She is cynical but not quite bitter – her life, all the details that she can remember so clearly, seems to have made her tired, although that may be the fact that she doesn’t sleep well and hasn’t really ever. She cuts quickly to the point and doesn’t hide her emotions, but she also has an easy, though often wry, laugh.

McGaugh likes to say – and it is written on a board in the lobby of the Center for the Neurobiology of Learning and Memory – that memory is our bridge to the future. But for Price, it doesn’t feel like that. “I’m paralysed, because I’m afraid I’m going to fuck up another whole decade,” she said. She has felt this way since 30 March, 2005, the day her husband, Jim, died at the age of 42. Price bears the weight of remembering their wedding on Saturday, 1 March 2003, in the house she had lived in for most of her life in Los Angeles, just before her parents sold it, as heavily as she remembers seeing Jim’s empty, wide-open eyes after he suffered a major stroke, had fallen into a coma and been put on life support on Friday, 25 March 2005.

But for all the terrible things that people with HSAM can never forget, there are also wonderful memories. When Petrella turned 50, he put together the Book of Bob, a catalogue of the most memorable days he has ever had, one for each calendar day of the year. “It’s totally uninhibited, it talks about sex, drugs, and rock’n’roll,” he said. “I didn’t hold back.” And when he recalls 15 April 1967, he gets a kind of glow and a grin – that was the day that 16-year-old Petrella sat on the rooftop of the local newspaper, where he wrote sports pieces and obituaries, and listened to a battle of the bands contest going on in the street below. He felt like the “king of the town”, he says. “I just felt so good. I just felt so good about my life. That was my second-best April. But a time like that, just sticks in my mind.”

When I first spoke to McGaugh, he told me that the real question at the heart of HSAM wasn’t why his subjects remember, but why we forget. “The overall summary of all of this is that they’re bad forgetters,” he said. And forgetting is what humans do; often what we need to do. The title character in Jorge Luis Borges’s story Funes the Memorious, who acquires a perfect memory as the result of an accident, can no longer sleep because he is kept awake by the thousand mundane memories that whined like mosquitoes in his ears. The “peculiar mixture of forgetting with our remembering,” wrote William James, one of the founders of modern psychology, “is the very keel on which our mental ship is built.” “If we remembered everything,” he continued, “we should on most occasions be as ill off as if we remembered nothing.”

https://www.theguardian.com/science/2017/feb/08/total-recall-the-people-who-never-forget?CMP=oth_b-aplnews_d-1

Two simple mind-body practices improved cognition and helped reverse perceived memory loss in older adults with subjective cognitive decline, in a pilot study published in the Journal of Alzheimer’s Disease.

Researchers randomly assigned 60 older adults with subjective cognitive decline—a strong predictor of Alzheimer’s disease—to a program of either beginner meditation (Kirtan Kriya) or music listening over 6 months. For the first 3 months, participants were directed to practice their intervention 12 minutes daily. For the remaining 3 months, participants were told to engage in their intervention at their discretion.

At 3 months, both the meditation and music listening groups showed marked and significant improvements in subjective memory function and objective cognitive performance, researchers found. What’s more, the substantial gains were maintained or improved at 6 months.

Brain Games Linked to Delayed Cognitive Decline in Elderly

“Findings of this preliminary randomized controlled trial suggest practice of meditation or music listening can significantly enhance both subjective memory function and objective cognitive performance in adults with subjective cognitive decline,” researchers concluded, “and may offer promise for improving outcomes in this population.”

Researchers had previously found that both interventions also improved sleep, mood, stress, well-being, and quality of life—with gains particularly pronounced in participants who practiced meditation. In that study, too, improvements were maintained or improved 3 months after baseline.

—Jolynn Tumolo

References

Innes KE, Selfe TK, Khalsa DS, Kandati S. Meditation and music improve memory and cognitive function in adults with subjective cognitive decline: a pilot randomized controlled trial. Journal of Alzheimer’s Disease. 2017;56:899-916.

Meditation and music may help reverse early memory loss in adults at risk for Alzheimer’s disease [press release]. Lansdale, PA: IOS Press; January 23, 2017.

by Lauren Gravitz

Imagine you’re the manager of a café. It stays open late and the neighbourhood has gone quiet by the time you lock the doors. You put the evening’s earnings into a bank bag, tuck that into your backpack, and head home. It’s a short walk through a poorly lit park. And there, next to the pond, you realise you’ve been hearing footsteps behind you. Before you can turn around, a man sprints up and stabs you in the stomach. When you fall to the ground, he kicks you, grabs your backpack, and runs off. Fortunately a bystander calls an ambulance which takes you, bleeding and shaken, to the nearest hospital.

The emergency room physician stitches you up and tells you that, aside from the pain and a bit of blood loss, you’re in good shape. Then she sits down and looks you in the eye. She tells you that people who live through a traumatic event like yours often develop post-traumatic stress disorder (PTSD). The condition can be debilitating, resulting in flashbacks that prompt you to relive the trauma over and over. It can cause irritation, anxiety, angry outbursts and a magnified fear response. But she has a pill you can take right now that will decrease your recall of the night’s events – and thus the fear and other emotions associated with it – and guard against the potential effects of PTSD without completely erasing the memory itself.

Would you like to try it?

When Elizabeth Loftus, a psychologist at the University of California, Irvine, asked nearly 1,000 people a similar question, more than 80 per cent said: ‘No.’ They would rather retain all memory and emotion of that day, even if it came with a price. More striking was the fact that 46 per cent of them didn’t believe people should be allowed to have such a choice in the first place.

Every day, science is ushering us closer to the kind of memory erasure that, until recently, was more the province of Philip K Dick. Studies now show that some medications, including a blood-pressure drug called propranolol, might have the ability to do just what the ER doctor described – not just for new traumas, but past ones too.

Granted, that future is not yet here. Most of the time, we’re still better at subconsciously editing our own recollections than any new technology is. But with researchers working on techniques that can chisel, reconstruct and purge life’s memories, it becomes crucial to ask: do we need our real memories? What makes us believe that memory is so sacrosanct? And do memories really make us who we are?

Many would argue that humans are driven by their stories. We create our own narratives based on the memories we retain and those we choose to discard. We use memories to build an understanding of self. We lean on them to make decisions and direct our lives.

But what happens to our sense of self if we purge the most distasteful memories and cherry-pick the good ones? When some things are hard to think about, or so injurious to our self-image, are we better off creating a history in which they no longer exist? And if we do, are we doomed to repeat our mistakes without learning from them, doomed to fight the same wars? By finding ways to erase our memories, are we erasing ourselves?

Our memories aren’t fixed. We already edit them: sometimes intentionally, sometimes not. Sometimes by ourselves, and sometimes when other people’s recollections filter into our own. We forget. We ‘remember’ incorrectly. We can even train our brains to remember facts and moments with greater acumen.

Think about your first kiss. No, go back further, to the first time you rode a bike. How clear is that memory? Is it picture-perfect or has it acquired a sepia tint and become a bit tattered around the edges?

The first time I balanced on a two-wheeler was in front of our little ranch-style house on a quiet street in northern California. I was perched proudly, if hesitantly, on the flowered banana seat of a shiny purple Schwinn that my father had just separated from its training wheels. ‘Don’t let go,’ I told my mom before we pushed off. She nodded and I started peddling as she grasped the rounded chrome handle on the back of the seat. ‘Don’t let go!’ I yelled again, and glanced back to find that she had, in fact, let go and was now half a block away, laughing and looking oh-so proud. I promptly fell. And then, because I’d scraped my knees, I started to cry. She came running up and I screamed at her, feeling betrayed.

At least, I think that’s what happened. Thirty-five years later I’m not so sure. Perhaps adult-me has re-interpreted what five-year-old me was feeling. Or perhaps, over the years, every time I pulled this memory up to the surface and told the story, I changed it ever so slightly, until what I remember now is more fiction than fact.

For decades, most memory researchers compared memories to photographs, and our brains to albums or filing cabinets stuffed full of them. They believed that each photo required an initial development period – much the way that pictures are processed in a darkroom – and then was filed away for future reference.

But in the past few decades, scientists have discovered that memory is far more plastic than that. It doesn’t just fade like a photograph tucked away in an album. The details subtly morph and shift. It’s malleable. And some research suggests it might be erasable.

Individual neurons communicate using chemicals called neurotransmitters, which flow from one neuron to the next across synapses – small gaps between the nerve cells. When memories are formed, protein changes at the nerve synapses must be consolidated and translated into long-term circuits in the brain. If consolidation is interrupted, the memory dissolves.

Different types of memories are stored in different places in the brain, and each memory has a dedicated network of neurons. Short-term memories such as a grocery list or an address live, briefly, in the pre-frontal cortex – the foremost area of the folded grey matter that encases the brain. Fear and other intensely emotional memories exist in the amygdala, while facts and autobiographical events are located in the hippocampus. But memories aren’t isolated in these different areas – they overlap and intertwine and connect and diverge like the tangled branches of an old lilac tree. Even when a factual memory fades it can leave an emotional trace behind.

In 2000, two neuroscientists at New York University, Karim Nader and Joseph LeDoux were studying memory in rats when they discovered that the very act of recalling a memory puts it at risk of being altered or possibly erased. When a rat is afraid, it freezes in its tracks. Nader trained his rats to associate a particular tone with a mild electrical shock – every time he played it for them, they froze. As much as a year later, they still froze whenever they heard it, proof that the memory had consolidated and remained intact. Then, he injected a drug that blocked protein formation into each rat’s amygdala, the brain’s emotional strongbox, and played them the same sound but this time without the shock. The next day, the animals had no reaction at all to the tone.

The results were the first to prove how it might be possible to alter a memory that had already been stored, says Nader, who’s now at McGill University in Montreal. ‘We showed that just by recalling a year-old memory, a circuit can go back to being unstored and has to be stored again.’ With each recall, the memory was being reconsolidated – a process akin to pulling a picture out of that album, telling a story about it, then trying to reposition it exactly as it was. But the drug disrupted that process, as though someone had closed the album and spirited it away before the photo could be replaced. Now, with nothing to reinforce the rats’ memories upon recall, the memories appeared to evaporate as though they had never existed.

Upon hearing about Nader’s research, one of his colleagues at McGill, the psychologist Alain Brunet, began looking into whether the finding could be applied to people with PTSD. This condition is less a problem of remembering and more of not-forgetting, when the mind repeatedly plays back a disturbing chain of events, each time prompting the same feelings of fear and distress that were present the moment it happened.

The drug that Nader injected into his rats isn’t approved for most uses in humans. But another one that blocks protein formation in the amygdala is inexpensive, safe, and readily available: the blood pressure-lowering drug, propranolol.

Brunet has now performed a number of trials in people with PTSD – with as few as one session and as many as six – and seen some intriguing results. By administering the pill, waiting an hour, then asking his subjects to write down the traumatic story in as much detail as they could remember, Brunet found that some who had suffered PTSD for years began to look back at the event and remember most of the details while feeling… well, not much at all.

Scientists think it might work like this: norepinephrine is a stress hormone, a neurotransmitter that enhances emotional learning in the brain. Propranolol blocks its effects, preventing its involvement in reconsolidation of the retrieved memory. ‘The reconsolidation blockade has potential to become a universal treatment for PTSD. And PTSD is a universal problem,’ Brunet told me.

Other researchers have tried to repeat Brunet’s work, with greater or lesser success. In two separate studies, led by Brunet and the Harvard psychiatrist Roger Pitman, ER patients who took propranolol within six hours after a trauma appeared protected from experiencing intensely physical reactions when they recalled the event a few months later. It was these studies that Loftus referenced when she created her thought experiment – and that her subjects believed should not be allowed to go any further.

Because propranolol can seemingly erase emotional fear without affecting factual memory, it also holds promise for other anxiety-related disorders. Last year, Merel Kindt, a psychology researcher at the University of Amsterdam, used the drug to help people with arachnophobia to overcome their fear of spiders. Although they clearly remembered being afraid, Kindt’s subjects could now touch and even hold a tarantula.

New studies continue to reveal ways in which memory reconsolidation might be helpful, and multiple mechanisms that could be exploited for memory editing. By disassociating addicts’ memories of being high from their fond feelings toward the experience, scientists have looked at the potential of propranolol to cure alcohol addiction in people, and have even tested it for treating heroin and cocaine addiction in rats. Others are interested in a different drug, called Blebb, to slice out methamphetamine-related memories.

If this same memory-dampening pill could be used to help addicts, would Loftus’s subjects feel differently about its value? Could a judge ethically order this kind of therapy for chronically troubled addicts? When is memory expendable for the good of an individual or of society? And why is it less tolerable to use medication to erase or suppress a memory than it is to rely on our own brains to do the work?

The human brain is remarkably flexible. Its ability to selectively prune our memories’ errant branches is a necessary adaptation. If we remembered every moment of every day, most of us would get too bogged down in our own minds to be functional. Psychologists believe that the human brain has evolved to forget the trivial stuff and highlight important episodes, especially negative ones, so that we might better predict future events and know how to handle them.

That can make trauma harder to expunge, perhaps for good reason. ‘Traumatic experiences give you an opportunity to think about who you are in the moment that life really disrupts you. They make you ask: “What kind of person am I? How did I get out of it?”’ says Kate McLean, a psychologist who specialises in narrative identity at Western Washington University in Bellingham.

‘Dealing with trauma is like strengthening a muscle. If you’ve done your bicep curls, the next time you have to lift a heavy box you can do it more easily,’ she says. ‘People who don’t deal with or who forget [trauma] are not necessarily less happy, but will they be able to deal with the challenges that come next?’ She postulates that they might. But, she says, they could also discover that this kind of temporary coping strategy has consequences up the road.

I have no need to remember what I had for lunch last Wednesday, nor what I wore to that REM concert in 1995 (and I probably don’t want to). I do, however, clearly remember how I lost my footing at the top of the 57th Street subway entrance and bumped down a flight of stairs to land in a wet, embarrassed heap. I will never again forget that metal stair treads get slippery in the rain.

As mortified as I felt, however, the experience doesn’t seem like something I’d want to erase from my memory. Even the most red-faced, shameful moments of my life aren’t something I want to forget: they make me who I am. They are my cautionary tales, my forehead wrinkles. They help me navigate relationships more tactfully and better predict potential outcomes.

If someone were to ask me how I felt about scrubbing away emotional memories, I’d advise them to think hard about it. After all, that’s what I did, and I might never forgive myself.

I am one of the people McLean’s warning is meant for, one of those people who at some point made a conscious decision not to deal with one of life’s challenges. I have a gaping hole in my memory where my father should be, the result of a particularly effective attempt at not dealing by my adolescent brain.

My father had multiple sclerosis. It wasn’t something I thought much about growing up, other than dedicating a sixth-grade science-fair project to describing the disease. It’s an autoimmune disorder of the central nervous system, in which damage to the protective nerve sheaths disrupts neural signalling. It can cause everything from vision problems to paralysis. For my dad, at first, it mostly meant bouts of dizziness and occasional weakness.

One January afternoon when I was 12, however, I walked in after school to see both of my working parents at home in the middle of the day. Something was clearly wrong. My father had caused a car accident that morning and, while both he and the person he’d hit were uninjured, he had no memory of how he got there – a neighbourhood in the opposite direction from his office – and remained confused about the gender of the other driver. It was our first clue that his disease was about to take a rare, devastating turn, and steal not only his mobility but his mind.

In a way, it stole my mind, too.

Within six months, my father – a toxicologist and epidemiologist with a PhD in biochemistry – was spending his workdays staring vacantly out of his office window. He went from a sharp and quick-witted (if occasionally acerbic) debate partner to someone who was dull and vacuous (if mostly pleasant). He displayed all the joy and petulance of a four-year-old and had trouble holding up his end of anything but the simplest conversations.

His body soon followed. The medications he took to help him walk caused terrible convulsions that left him shaking on the floor. A lifelong smoker, he’d light a cigarette and then forget he was holding it, sometimes singeing the tips of his fingers or, once, dropping it in the bathroom where it melted a hole in the linoleum. Within months, he progressed from cane to walker to wheelchair, and eventually had so much trouble swallowing he required a gastric feeding tube for nutrition and a Styrofoam cup to spit into so he wouldn’t choke on his own saliva.

I remember all of this quite clearly. I remember that damned Styrofoam cup, the shiny blue of his wheelchair, the glassy look in his eyes. I remember how he hardly recognised me but how he lit up with the purest smile when my mother entered the room. And despite the fact that I was almost a teenager when the disease began to ravage my father, despite 12 years of prior history dense with family trips and holidays, despite a nightly tradition reading The Hobbit and other books aloud together before bed, I do not remember what my dad was like before he lost his mind.

It’s not that I don’t remember doing all those things – I do. I just can’t remember him. On the day of that first bike ride, even though he had just taken the training wheels off my purple Schwinn, I have no idea if he was standing next to my mother when I fell or if he was even there at all. It’s as if I have taken a scissor to my memories and sliced him right out of the photographs.

At the time, I did it quite intentionally. Every time my mother started to ask: ‘Do you remember when your father…’ I would cut her off abruptly. ‘I don’t want to talk about it,’ I’d say. Then I’d force my brain to bounce past it like a stone skipping off a pond and focus instead on something less painful, usually the man he had become. Rather than dwelling on the father I’d lost, my teenage brain lessened the heartbreak by replacing him with the man who sat in that blue wheelchair. Decades later, I can’t remember him as anything else, no matter how hard I’ve tried.

According to Michael Anderson, a neuroscientist at the University of Cambridge, I did something called ‘retrieval suppression’, in which someone intentionally takes mental action to prevent remembering something unpleasant – a process facilitated by the prefrontal cortex. So far, the emotional stronghold of the amygdala is what researchers understand best when it comes to memory suppression. Yet it’s my hippocampus, the area where factual memory lies, that seems to have the (figurative) holes. Intentional suppression works because we engage the brain’s prefrontal cortex to help us temporarily interrupt hippocampal function, briefly preventing it from encoding or consolidating memories.

Psychologists have long suggested that this kind of memory suppression takes a toll. According to Freud, memories pushed deep into the subconscious mind continue to influence a person’s thoughts and actions long into the future.

But Anderson has found that suppressing a memory also suppresses its subconscious effect on behaviour. He uses a procedure dubbed ‘think/no-think’ to better understand suppression in his study volunteers: first he shows them a picture or a word, then he directs them to either think about it or to intentionally shut down the retrieval process. To look specifically at its effect on behaviour, he and his colleagues asked volunteers to learn a set of word-picture pairs so that a word would prompt them to think of the coupled object (be it a motorcycle or a potted plant). But if the word itself was in red, they told participants to intentionally suppress any thought of the associated object when it popped to mind. When the researchers later showed them pictures of the objects, their subjects had a slightly harder time identifying them.

Some clinicians take the stance that memory suppression can be unhealthy, but this may be based on false assumptions, Anderson says. ‘Maybe it’s not a bad idea to suppress them after all. By giving unwanted memories undue attention, you could ensure they continue to stick around.’

Earlier this year, using the same think/no-think technique, he found that intentional suppression creates what he calls an ‘amnesic shadow’, one that spreads beyond the unwanted memory like a tree pruned a bit too enthusiastically. Participants in Anderson’s trial found that not only were they unable to remember objects they were trying to suppress, they were also less likely to remember objects they learned shortly before or after one they tamped down. It’s a finding that helps explain why people who experience harrowing car crashes and other distressing events often can’t remember what immediately preceded the trauma. It could also help explain why I have so few memories of doing anything at all with my father.

Those memories might not be gone forever. A recent study in the neurologically simple sea slug indicates that interrupting reconsolidation might not be erasing memories but instead simply blocking our access to them. David Glanzman, a neurobiologist at the University of California, Los Angeles, has found that when neurons of the sea hare known as Aplysia californica are transferred to a petri dish, they can be trained much like Nader’s shocked rats. And as with those rats, when Glanzman and his colleagues triggered a memory of the shock and then dosed them with a drug that blocks protein formation, a number of synapses disappeared. But the synapses that dissolved appeared to be random – they weren’t necessarily those associated with the shock. When the researchers went back to the intact animals to see if they could reinstate the shock memory, they found that just a few shocks were enough to restore memories that should have been completely erased. This told them that the memory was located outside the synapses; they traced it to the cell’s nucleus, a part of the neuron that remains intact even as synapses come and go. Deep within the brain, or at least in the brain cells of a sea hare, memories persist.

Yet knowing this, knowing someone could one day tell me that they had found a way to grant me access to my memories of my father, I’m no longer certain I would try.

I spent years trying to find those memories. I asked relatives and friends for stories. I stared at faded family pictures trying to infuse them with the personality and warmth that comes only from the act of reminiscing. But perhaps all this time I’ve been looking for the wrong thing. Perhaps it’s okay to let the memories go. Over time, my sliced-up memories have defined my personal understanding of self and have, ever so gradually, become part of a narrative I’m no longer sure I want to change.

Yes, my over-pruned tree is missing some branches and appears rather lopsided. Its flowers don’t always open the way they should. But it’s also sprouting new leaves in places I never expected, and its crooked visage is simply part of who I am. Rather than trying to fill those empty holes, I can now look at the negative space and see it – all of it – as a part of me.