You park your car. You lock it up, grab your bag from the trunk, and head into work. As you do, your brain quietly gets in high gear, racing like it’s in the Indy 500. Even though it seems you’re hardly thinking about where you activated your parking brake, nerve cells in your gray matter, in a region called the entorhinal cortex, are chattering about it. Those cells, called neurons, send chemical compounds across synapses, the empty spaces between cells. Once across the gap, the compounds, known as neurotransmitters, bind to receptors on the surface of the receiving cell, sending news that your Lime Squeeze Ford Fiesta is on the pothole-scarred second floor of the garage, on the side that leads back out toward the exit, the one with the view of the water.
The “message” sets off a chain reaction that chemically changes neurons into ones that remember. One nerve cell can make connections with 10,000 others, so news of your humdrum, workaday parking experience excites your memory centers in an instant, shuttling signals from the entorhinal cortex to a small channeling area called the perforant pathway. The trail of neurochemical bread crumbs ends, temporarily at least, in a central brain outpost called the hippocampus. A memory of your morning parking spot parks itself there. If you were to stay at work for a couple of weeks, the memory might travel even further, to the brain’s neocortex, where it would be stored for long-term use.
But after just a long day that leaves you hungry, stressed, and tired—all states that can be the enemies of memory—your healthy hippocampus nonetheless remembers. In the dentate gyrus and CA3, wee parts of the hippocampus, neurons fire, calling up associations (the water view, the pockmarked second floor) that will lead you back to your car. With nearly no conscious effort from you, your brain’s circuitry has told you where to go.
We rely on this system of instant recall hundreds of times every day. It reminds us of things large and small—anniversaries, appointments, how to do our jobs. And even in an age when we outsource much of our memory to our digital appendages—our computers, electronic calendars, and mobile phones—we call upon our analog, though hardly low-tech, memory centers more than ever, as the world presents us with more and more things to remember (including those blasted passwords). Chasing our memories often takes time, and even if our brains are fine-tuned, we’re not always as successful as we’d like to be at it. If you add up the hours we spend each year tracking down things we’ve mislaid or otherwise forgotten about, we’re talking days, perhaps even weeks, sucked away into the gaps in our memory.
Forgetfulness can mean more than inconvenience and frustration, however. If we lose our network of memories—of whom we relate to, where we’ve been, our predilections, our past—we lose something else: our selves. Imagine who you’d be if the pathways to your hippocampus had begun to break down. What if the synapses didn’t connect, short-circuiting the system that keeps you sensible and sentient? Who would you be without the reminiscences that unfold the narratives of your life?
Memory can present us with other shocks. Imagine just the opposite of the previous scenario: recollections, in the form of neurotransmitters and receptor chemicals, that have burned their way into neurons not just in the hippocampus but the amygdala, the brain’s house of horrors, during a traumatic event. The quality of your life would be dashed by constantly recalling those memories—ones you can’t shake—forcing you to relive a crystalline moment of utter terror. Memory, like forgetting, can incapacitate.
Although research scientists who track down memory have hardly unmasked all facets of its nature, they have unlocked a storehouse of secrets during the last 25 years, firing off discoveries at an unprecedented rate. Those breakthroughs have given us more clues as to how and why we remember, the indispensable role memory plays in learning, and how disease nixes or amplifies how we recall things. Faced with the urgency of a growing number of Alzheimer’s disease sufferers and aided by the federal grant money that has swelled along with it, scientists who study the brain at the cellular and molecular level say that studying how disease short-circuits memory has led them to new insights into how our brains call things up. Many researchers, including several at Johns Hopkins, have begun to move beyond the ABCs of recollection, offering potential treatments or the prospect of new drugs that could help us hold on to remembrances of things past and erase memories that are so painful they can harm our mental health.
With the help of emerging high-tech machines and computer software that allow them to watch how the wheels of the brain turn, researchers say they are much closer to answering a question that has so far stumped an aging nation, as the number of people with Alzheimer’s disease has climbed above 5 million: How can we maintain mindfulness?
YOU PARK YOUR CAR. You lock it up, grab your bag from the passenger seat, and head into the grocery store. As you do, your brain tries to record where your car will be when you get back. But its old failsafe mechanisms have become worn down over time. In your brain, the connections between the entorhinal cortex and the hippocampus have grown tenuous. Later, when you roll your grocery cart outside, you freeze, terrified that you’ve drawn a blank as to where you left your car. Your brain tries to ramp itself up—activity levels in the hippocampus increase. Yet for all of that extra brain work, all you’re recalling are older memories of where your car is—or was. Information that would otherwise be transmitted across synapses never made the leap. Your brain never fully registered the spot you pulled into, leaving you embarrassed and fretful.
You could be suffering from mild cognitive impairment, a disorder that can precede full-blown Alzheimer’s. Or you may have Alzheimer’s itself, in which case you will eventually have trouble not only locating your parked car but, as time passes, remembering its make, what it looks like—even what a car is.
To understand how this happens, scientists at Johns Hopkins run three-dimensional functional magnetic resonance imaging, or fMRI, brain scans on older people. On a memorably hot summer morning at the Johns Hopkins–affiliated Kennedy Krieger Institute, Arnold Bakker, A&S ’11 (PhD), conducts an fMRI on a 65-year-old woman with symptoms of mild cognitive impairment—forgetfulness, a decreased ability to take in and retain new information. After he eases her into the center of a state-of-the-art 3 Tesla MRI machine—which he calls “a $3 million doughnut”—he shows her a series of pictures that test her ability to separate one pattern from another, a key to creating new memories. Bakker, an assistant professor of psychiatry, peers in at a computer image of the woman’s brain. “This slightly curved structure in the center”—he points to a semi-rectangular region two inches long—“is the hippocampus.” The machine scans the blood and glucose activity in certain parts of the brain as study participants try to separate new, old, and similar images from one another. Those scans will tell researchers a lot about how well their subjects’ memory systems are working.
When memory circuits hum along, they quickly pile up enough information to allow us not only to recall things but to learn. They exemplify the neuroscientific concept of plasticity—our brains’ ability to grow and change. “Memory is a change in the strength of synaptic connections,” says Michael Yassa, A&S ’02, ’05 (MA), an assistant professor of psychological and brain sciences at the Krieger School of Arts and Sciences. “It allows us to build knowledge.”
But as synapses in aging brains weaken, absentmindedness follows. Information is less likely to travel across adjacent neurons. In particular, the perforant pathway, which connects the hippocampus to the rest of the brain, breaks down, leading to memory loss.
Although the answers subjects give during fMRI tests could be used to confirm a diagnosis of cognitive impairment or Alzheimer’s disease, researchers aren’t primarily interested in individual cases. The study aims to compare the efficiency of the memory centers of those who are having problems with others who aren’t. “For us, it’s not so much the answers that they give as how their brains respond to stimuli,” says Bakker.
Yassa—who has conducted a similar ongoing study for the past two years—says that younger people can readily sort out the different categories of images. But in people age 60 to 80 with healthy brains, the hippocampus showed activity consistent with the “already seen” images when participants were shown new pictures that were slightly different from ones they had already seen. Their brains didn’t create new memories of the new, if only slightly novel, images. “They fell for our trick,” says Yassa. “That’s partly because, with age, hippocampal plasticity breaks down.”
Until a decade or so ago, neuroscientists thought that people lost their capacity to remember as they aged because of the death of neurons. But researchers at Johns Hopkins and elsewhere found that cell death is not the culprit, at least not initially; loss of synaptic function is. “Cells don’t die, but they lose their ability to communicate with each other,” Yassa says. “As you lose the connections between the hippocampus and the rest of the brain, the hippocampus becomes isolated and memory starts to fail.”
What’s more, in memory-challenged brains, a particular region in the hippocampus called CA3 creates its own interference, emitting more electrical and chemical activity when we try to recall something. This makes it harder for new information to stick. “It’s like a synaptic feedback loop,” says Yassa. “There’s this clutter. The more activity there is in CA3, the more interference there is.” The problem for memory is that clutter in the hippocampus leaves it stuck in retrieval mode—it tries repeatedly to get at an old memory instead of doing what it is supposed to do: create new ones. Its ability to separate similar patterns wanes. “The clutter won’t let the hippocampus listen to the new information,” Yassa explains.
When synaptic function breaks down in people who suffer from disease, such as Alzheimer’s, the death of neurons in the hippocampus follows. Eventually, neurons in the brain’s other memory centers—the amygdala, cerebellum, and cortex, among others—die as well. The result is a steep downhill fall with no cure or treatment.
That phenomenon was first noted during observations of rats made by Michela Gallagher, a professor of psychological and brain sciences at the Krieger School. Gallagher has studied the nature of memory in rats, mice, and humans for the past 25 years, creating a rat study model that is used by memory and learning researchers around the world. In the 1990s, she became one of the first scientists to note that neuronal death wasn’t likely to be the initial cause of memory problems.
Bakker and Yassa, onetime students of Gallagher’s, are now her colleagues. Besides trying to get at the basics of memory, the duo is investigating whether a potential remedy for forgetfulness discovered by Gallagher might calm an excessively busy hippocampus and possibly stave off brain disease in the aged. By repurposing an epilepsy drug called levetiracetam for use in people with the earliest signs of impaired memory, Gallagher and her research mates hope to forestall the debilitating effects of Alzheimer’s. A small study conducted early this year found that people with mild cognitive impairment remembered significantly better when given low doses of levetiracetam. Each year, 15 percent of people diagnosed with mild cognitive impairment go on to develop Alzheimer’s.
The early results, which Bakker and others are now trying to replicate in studies involving larger groups of people, could prove to be groundbreaking. In the case of Alzheimer’s, postponing its arrival is enough to spare many the ravages of it, as people die of other unrelated causes. “There’s very strong evidence that if you could delay the onset of Alzheimer’s by even one or two years, you could save people a lot of pain and society a lot of money,” says Richard O’Brien, an associate professor of neurology at the School of Medicine. “We don’t need a home run, an outright cure. We just need a solid double, something that delays the onset.”
As a clinician at the Johns Hopkins Bayview Medical Center, O’Brien regularly sees people each year suffering from memory loss. It pains him that medical science has yet to come up with an answer, or at least some glimmer of hope. “What we’re giving people now is junk,” says O’Brien. “We’re really educating families, not treating patients.”
Pharmaceutical companies have spent billions of dollars in recent years on drugs that boost a key neurotransmitter for memory, called acetylcholine, and others that attack the beta-amyloid plaques and tau proteins that tie memory up in neural knots. But they have yet to hit on a drug that could do more than mildly improve memory for a few months. Making things even more complicated is an emerging theory that views beta-amyloid and tau as signs of an aging brain and not necessarily of Alzheimer’s. Seven in 10 people whose autopsied brains contained plaques and tangles had never shown outward signs of dementia.
In the last two years, drug makers have run into a wall, with five major potential treatments flopping in clinical trials. Finding a remedy for brain diseases has always been difficult. Any drug that would involve the brain costs more to develop and takes years longer to test than drugs that treat other parts of the body because the effects of drugs on the human central nervous system take much longer to measure than, say, the effectiveness of antibiotics. Would-be brain drugs are also more closely scrutinized by federal regulators than most other types of drugs because of the harm they can do. The thorniness involved in developing drugs to treat the brain has left many companies tackling Alzheimer’s with serious financial problems. Some have dropped out altogether. “It might take 20 years to do a study to see how an anti-Alzheimer’s drug might work,” says O’Brien.
Other studies only hint at nonmedical methods for lowering the odds of coming down with Alzheimer’s. Some have shown that exercise can make a difference in reversing the brain plaques that attend Alzheimer’s—but only in mice. While long-term exercise may help humans avoid the disease, it may not help people once they have already begun developing it—perhaps 10 or more years before symptoms show up. “I joke with my patients that if they were mice I could cure them,” says O’Brien. “The mood in this field is very dark these days.”
Johns Hopkins scientists combat Alzheimer’s from a number of angles. Pathologists dissect the brains of people who have participated in the Baltimore Longitudinal Aging Study for clues as to why, for many, the capacity to remember disintegrates. Long-term studies involving the children of people who suffered from Alzheimer’s look at the disease from a genetic angle. Other researchers investigate ways to help the families of Alzheimer’s patients, or test existing drug treatments and the effects of exercise, or look into whether the disease can be pinpointed early on using a collection of biomarkers.
But no approach has created the buzz that Gallagher’s work has. Because she is testing a drug that has already been approved for use in treating epilepsy, even skeptics are guardedly hopeful. Because levetiracetam has already been federally OK’d for one use, it should take a considerably shorter time to test the drug’s effect against memory loss in humans—and, if proven safe, get it to market. People with epilepsy have experienced few problems with the drug at much higher dosages than Gallagher’s subjects were given. A concurrent study using the same antiseizure drug—conducted recently by a University of California, San Francisco, researcher—found that it works to reverse memory loss in mice bred to develop a genetic form of Alzheimer’s. Gallagher has already seen the drug work in rats. “Now’s the time to do a bigger trial on humans and see if all these accumulated results add up to anything,” she says.
To shepherd the drug through trials, Gallagher founded her own company. If all goes as planned, a larger drug firm will help her bankroll the costs of doing advanced human trials in the next few years, which will likely cost millions of dollars. Gallagher also has stepped down as vice provost for academic affairs to oversee levetiracetam’s development. “There’s so much going on right now,” she says. “I was telling another researcher as we were getting some of our early results that I don’t need to skydive. Life is exciting enough these days.”
ONLY IN MODERN TIMES have we seen an explosion in Alzheimer’s cases. Medical students in the 1950s and ’60s were told they might never see one, as the disease was considered rare. Among younger patients, it still is; people 60 and younger make up only 5 percent of all Alzheimer’s cases. But as Western populations have aged, the number of Alzheimer’s sufferers has skyrocketed.
Even before the days when people lived long enough to lose a lifetime of memories, humanity had reason to treasure its power of recall. We’ve long been wired by evolution to seek out rewards—food, drink—and in a specific way. It was extremely important for hunter-gatherers, for example, to know which plants were poisonous, which animals gathered where, and which creatures were capable of lethal attack. People honed these survival skills with the aid of memory. And they remembered to pass them down. Communal lore and rules of living were passed from generation to generation.
As humankind marched toward civilization, brain memory continued as the lone repository of knowledge. In the days before widely produced paper and the printing press, people worked to remember huge blocks of information. In ancient Rome and during the Middle Ages people constructed “memory palaces” in their minds—imaginary buildings where they could stow away words and objects, which they could retrieve later as they mentally walked through those places to recall lines from epic poems, prayers, and speeches. So valued was memory that scholars of yore believed that only by absorbing things thoroughly through memorization could one truly learn them. The idea that memory served as a perfect audiovisual recorder persisted through the better part of three millennia.
It wasn’t until the 20th century that scientists began to home in on something we now accept as fact: Memory is imperfect. Each time we recall something, the chemicals involved in summoning it up change it a bit, funneling the memory more deeply inside the fabric of our ongoing narrative, our autobiography. Most memories also travel through what scientists call “the curve of forgetting.” Even as we remember something, our grasp of it begins to lapse until eventually it is no longer a memory. Retrieving it is an inexact science—more like an art, actually. It is a creative act, one that can tend toward the fictive.
As much as we’ve evolved to trust our memory, then, we can’t rely on it entirely. This is why much of the memory we tap today exists in external appendages of the brain, such as the BlackBerry, GPS, Google, or Wikipedia. Unlike people 600 years ago and beyond, we know we can’t always trust our memories to serve us, especially when there’s so much more written down and encoded elsewhere than our brains could possibly remember. Scientists are just beginning to examine how outsourcing memory affects the way our brains develop.
Within the past generation, many of us have gone from memorizing the phone numbers of family and friends to merely plugging them into our cell phones and “forgetting” them, while remembering only where we encoded them. (Machines have become extra hippocampuses.) Too often, however, memories not only remain true, they beg our psyches for attention. Especially embarrassing moments or instances when we’ve felt threatened come flooding back again and again, no matter how hard we might want to offload them onto a disk drive, or shove them off a cliff.
YOU PARK YOUR CAR. After spending the day at work, you remember precisely that you left it on the second floor, facing toward the exit. As you use your remote key to pop the trunk so you can put your bag away, the car blows up, launching you into the concrete wall behind you. Battered and bleeding, you wonder whether you’ll live, and who is out to get you. The sensations of the scene—the obliterated car, the searing pain—trigger the amygdala, the brain’s seat of emotions, where the shock of the event will continue to resound. The hippocampus will record all those precise details. For the next 48 hours, your brain will be flooded with protein molecules called AMPA receptors (AMPARs) that will make the event unforgettable. The persistence of memory will become your enemy. Surrealistic shards of the event will live on in your fitful sleep and during unrelenting anti-reveries. What is going on?
The amygdala, an almond-shaped region of the brain that sits just in front of the hippocampus, reacts to trauma with a fear response that charges the neural circuitry, while other parts of the brain work to inhibit the fear. The problem in people suffering from post-traumatic stress—about 8 million in the United States—is that the amygdala and the lingering memory stored in the hippocampus continue to reign.
“Often, therapists can modify people’s responses to traumatic events through behavioral therapy, but relapse is very common,” says Richard Huganir, professor of neuroscience at the School of Medicine, adding that the memory of the event is not completely “erased” during such therapy. “The problem is that the fear response can be summoned up long after the fear conditions have been removed.”
Last year, Huganir and postdoctoral fellow Roger Clem published results of research on experimental mice, in which the duo investigated the role AMPARs play in keeping our waking nightmares alive. They found that the receptors increase during the so-called fear-conditioning period, which peaks at about 24 hours after trauma and dissipates at around the 48-hour mark. AMPARs, unlike most substances in the brain, are unstable and can conceivably be removed from cells. It’s possible that a drug could be developed to block and sweep away receptors that make fear indelible in the mind.
Huganir hopes that his and other Johns Hopkins scientists’ findings on the functions of brain chemicals will lead to treatments, likely many years down the road, that will quell the symptoms of post-traumatic stress disorder. They could include a drug given within 24 hours of an event, or possibly even later, that would fundamentally erase the fear associated with certain memories. “We’ve found that we can reactivate this window of therapeutic opportunity considerably [in mice], even seven days following a traumatic event,” Huganir says. Other diseases might benefit from the research as well. “We absolutely think the same principles we found for fear are relevant for drug addiction and possibly other neuropsychiatric disorders,” Huganir adds.
Another aspect of Huganir’s work, examining the genes behind the molecular basis of memory, spotlights an emerging pathway between research into memory and forgetting. A gene called KIBRA—so named because it is expressed in the kidney and the memory centers of the brain—has been linked to fear conditioning in mammals and plays a role in regulating AMPARs. But KIBRA also works in some people to underpin the brain’s ability to change and learn—it is key to the plasticity of synapses. “KIBRA is a ‘smart gene,’ a genetic variant that about 25 percent of the population carries that allows their memory centers to perform better than average,” he says. “There’s some evidence that people with that variant will develop a protective measure against disorders like Alzheimer’s disease.” A recent study by Huganir and colleagues found that mice that had the KIBRA gene removed from their systems were forgetful and slow learners—an indication that the gene is vital to the maintenance of strong memory.
Findings like that will help researchers navigate the developing trail that leads back and forth from the building blocks of memory to disease. For Huganir and others, this marks a new era of discovery in brain research.
“For years, there has been a divide between those who studied Alzheimer’s and those who looked at memory,” says Huganir. “Now, a lot of us who work on normal memory—on the cellular and molecular workings of synapses, for example—realize that we’re talking about the same genes that Alzheimer’s researchers are. If you know how a molecular gene is affected by disease, then biologists can use that gene to experiment and see how it functions normally. It’s opened things up for us.”
Michael Anft is Johns Hopkins Magazine’s senior writer for science and medicine.
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