Sleep boosts ability to learn language,

Scientists at the University of Chicago have demonstrated that sleeping has an important and previously unrecognized impact on improving people's ability to learn language.

Researchers find that ability of students to retain knowledge about words is improved by sleep, even when the students seemed to forget some of what they learned during the day before the next night's sleep. This paper, "Consolidation During Sleep of Perceptual Learning of Spoken Language," is being published in the Thursday, Oct. 9 issue of the journal Nature. The paper was prepared by researcher Kimberly Fenn, Howard Nusbaum, Professor of Psychology, and Daniel Margoliash, Professor in Organismal Biology and Anatomy.

"Sleep has at least two separate effects on learning," the authors write. "Sleep consolidates memories, protecting them against subsequent interference or decay. Sleep also appears to 'recover' or restore memories."

Scientists have long hypothesized that sleep has an impact on learning, but the new study is the first to provide scientific evidence that brain activity promotes higher-level types of learning while we sleep.

Although the study dealt specifically with word learning, the findings may be relevant to other learning, Nusbaum said. "We have known that people learn better if they learn smaller bits of information over a period of days rather than all at once. This research could show how sleep helps us retain what we learn."

In fact, the idea for the study arose from discussions Nusbaum and Fenn had with Margoliash, who studies vocal (song) learning in birds. "We were surprised several years ago to discover that birds apparently 'dream of singing' and this might be important for song learning," Margoliash said.

"Ultimately, our discussions stimulated a research design first proposed by Kim Fenn. The interdisciplinary nature of the research and the free exchange of ideas between animal and human work is also very exciting for us," Margoliash added.

For their study, the team tested college student understanding of a series of common words produced in a mechanical, robotic way by a voice synthesizer that made the words difficult to understand. They first measured the students' ability to recognize the words. They then trained them to recognize the words and then tested them again to see how effective the training was.

None of the students heard the same word more than once, so they had to learn how to figure out the pattern of sounds the synthesizer was making. "It is something like learning how to understand someone speaking with a foreign accent." Nusbaum said.

The team tested three groups of students. The control group was tested one hour after they were trained and recognized 54 percent of the words, as opposed to the 21 percent they recognized before training.

The scientists next trained students at 9 a.m. and tested them at 9 p.m., 12 hours later. During that time, the students had lost much of their learning and only made a 10 percentage point gain over their pre-test scores.

A third group was tested at 9 a.m. after having been trained at 9 p.m. After a night's sleep, those students improved their performance by 19 percentage points over their pre-test scores.

The students who were trained at 9 a.m. were tested again after a night's sleep, and their scores improved to the same level as the other students who had had a night's sleep.

"We were shocked by what we found," Nusbaum said. "We were particularly intrigued by the loss of learning the students experienced during the day and then recovered."

Researchers could not determine if the reduction in performance during the day was due to students forgetting what they'd learned, their listening to other speech or their thinking about unrelated issues during the day.

"If performance is reduced by interference, sleep might strengthen relevant associations and weaken irrelevant associations, improving access to relevant memories," the authors write. If information was forgotten, sleep might help people restore a memory.

Margoliash said, "Although these initial results cannot explain what is lost during the day, the question is very amenable to follow-up experiments."

Fenn added, "We are currently considering an FMRI study to investigate brain activity at the end of a day's learning compared with activity patterns after a night's sleep."

Contact: Catherine Gianaro
University of Chicago Medical Center
8th October 2003

Sharper minds

It would be hard to imagine improving on the intelligence of computer engineer Bjoern Stenger, a doctoral candidate at Cambridge University. Yet for several hours, a pill seemed to make him even brainier.

Participating in a research project, Stenger downed a green gelatin cap containing a drug called modafinil. Within an hour, his attention sharpened. So did his memory. He aced a series of mental-agility tests. If his brainpower would normally rate a 10, the drug raised it to 15, he said.

"I was quite focused," said Stenger. "It was also kind of fun."

The age of smart drugs is dawning. Modafinil is just one in an array of brain-boosting medications — some already on pharmacy shelves and others in development — that promise an era of sharper thinking through chemistry.

These drugs may change the way we think. And by doing so, they may change who we are.

Long-haul truckers and Air Force pilots have long popped amphetamines to ward off drowsiness. Generations of college students have swallowed over-the-counter caffeine tablets to get through all-nighters. But such stimulants provide only a temporary edge, and their effect is broad and blunt — they boost the brain by juicing the entire nervous system.

The new mind-enhancing drugs, in contrast, hold the potential for more powerful, more targeted and more lasting improvements in mental acuity. Some of the most promising have reached the stage of testing in human subjects and could become available in the next decade, brain scientists say.

"It's not a question of 'if' anymore. It's just a matter of time," said geneticist Tim Tully, a researcher at Cold Spring Harbor Laboratory on Long Island, N.Y., and developer of a compound called HT-0712, which has shown promise as a memory enhancer. The drug soon will be tested in human subjects.

The new brain boosters stem in part from research to develop treatments for Alzheimer's disease, spinal cord injuries, schizophrenia and other conditions. But they also reflect rapid advances in understanding the processes of learning and memory in healthy people.

Developing research

In the last two decades, scientists have made important discoveries about which regions of the brain perform specific functions and how those regions work together to absorb, store and retrieve information. Researchers also have begun to grasp how and where neurotransmitters are manufactured and which ones help perform which mental tasks.

"There are things cooking here that couldn't have been done one to two decades ago," said James L. McGaugh, director of UC Irvine's Center for the Neurobiology of Learning and Memory.

Research has gotten further stimulus from a deep-pocketed investor — the U.S. military, which is looking for ways to help pilots and soldiers stay sharp under the stress and exhaustion of combat.

The potential market for cognitive enhancers has never been bigger, or more receptive.

An estimated 77 million members of the baby boom generation will turn 50 in the next 10 years, joining 11 million who have already passed the half-century mark — a stage at which memory and speed of response show noticeable decline.

Modafinil, the drug that whetted Stenger's powers of concentration, is used to treat narcolepsy and other sleep disorders. It is one of three prescription medications on the market that have been shown to enhance certain mental powers.

The other two are methylphenidate, marketed under the name Ritalin as a remedy for attention deficit disorder, and donepezil, prescribed for patients with Alzheimer's.

Studies have shown that these drugs can produce significant mental gains in normal, healthy subjects. None of the three has been approved for that purpose. Nevertheless, a growing number of healthy Americans are taking them to get a mental edge.

Some obtain the medications from doctors who write prescriptions for "off-label" uses not approved by the Food and Drug Administration — a practice both legal and common. Others buy the drugs through unregulated Internet pharmacies.

Cambridge University psychologist Barbara Sahakian considers modafinil (marketed commercially under the name Provigil) especially intriguing. Its developers aren't sure exactly how it keeps drowsiness at bay. But even in healthy people, the medication appears to deliver measurable improvements with few side effects.

In a series of experiments in 2001, Sahakian and colleagues found that in games that test mental skill, subjects who took a 200-milligram dose of modafinil paid closer attention and used information more effectively than subjects given a sugar pill.

Confronted with conflicting demands, the people on modafinil moved more smoothly from one task to the next and adjusted their strategies of play with greater agility. In short, they worked smarter and were better at multi-tasking.

"In my mind, it may be the first real smart drug," Sahakian said. "A lot of people will probably take modafinil. I suspect they do already."

Donepezil, sold under the name Aricept, also has been found to boost the brain function of healthy people. The drug increases the concentration of a neurotransmitter called acetylcholine, boosting the power of certain electrical transmissions between brain cells.

In a 2002 study, 18 pilots with an average age of 52 were put through seven training flights in a simulator and taught a complex set of piloting skills over 30 days. Half took a low dose of donepezil; the other half took a placebo. At month's end, all were tested on the skills they had learned.

The pilots on donepezil retained more of the skills than those who took the placebo. On the most challenging parts of the test, an emergency drill and a landing sequence, their performance was notably superior, according to results of the study published in the journal Neurology.


Botox for the mind?
Some scientists predict that the development of even more-effective brain-enhancing drugs will usher in an age of "cosmetic neurology."

"If people can gain a millimeter, they're going to want to take it," said Jerome Yesavage, director of Stanford University's Aging Clinical Research Center and an author of the donepezil study.

Judy Illes, a psychologist at Stanford's Center for Biomedical Ethics, said mind-enhancing medicine could become "as ordinary as a cup of coffee." This could be good for society, helping people learn faster and retain more, she said.

But it also raises questions: Will the rich get smarter while the poor fall further behind? (Drugs such as modafinil can cost as much as $6 per dose.)

Will people feel compelled to use the medications to keep up in school or in the workplace? In a world where mental function can be tweaked with a pill, will our notion of "normal intelligence" be changed forever?

Mirk Mirkin of Sherman Oaks, 77, a retired marketing manager, would like to regain a bit of his old intellectual nimbleness. A member of Mensa, a society for people with IQs in the top two percentile of the nation, Mirkin is bothered by what he laughingly calls "senior moments," such as when a name stubbornly eludes him.

If a pill could halt the march of forgetfulness without uncomfortable side effects, he would probably take it, Mirkin said.

Mirkin, who proctors tests for admission into Mensa, said he would not object if younger people took such pills to pump up their mental muscle for the test. "If they physically can handle it and want it bad enough, why not?"

Many college and graduate students want an edge bad enough to take Ritalin, even if they do not suffer from attention deficit disorder.

At campuses, test sites and, increasingly, workplaces across the country, people are popping "vitamin R." Some users persuade a doctor to prescribe it; others get it from friends who have been diagnosed with attention deficit disorder.

The growing demand for Ritalin, which can be addictive, has prompted the U.S. Drug Enforcement Administration to classify it as a "drug of concern."

On the Internet chat board of the Student Doctor Network, college students preparing for medical school admission tests frequently discuss the benefits of taking Ritalin or similar drugs on exam day.

Some students think they have no choice. "You figure you're being compared to people who are on Ritalin," said one Los Angeles student who frequents the site and recently asked a relative to supply the drug. "I just figured it would be more fair if you're on the same level."

Eventually, ambitious parents will start giving mind-enhancing pills to their children, said McGaugh, the UC Irvine neurobiologist.

"If there is a drug which is safe and effective and not too expensive for enhancing memory in normal adults, why not normal children?" he said. "After all, they're going to school, and what's more important than education of the young? And what would be more important than giving them a little chemical edge?"

Defense Department scientists are pursuing just such an advantage for U.S. combat forces. The Pentagon spends $20 million per year exploring ways to "expand available memory" and build "sleep-resistant circuitry" in the brain.

Among its aims: to develop stimulants capable of keeping soldiers awake, alert and effective for as long as seven days straight. The armed forces have taken leading roles in testing modafinil and donepezil as performance enhancers for pilots and soldiers.

On the horizon are other potential smart drugs, each operating on different systems in the brain. If they progress through tests of safety and effectiveness, the first of them could be available as early as 2008. (See "What's on the horizon?").

Three companies are among the leading contenders in the race to develop drugs for memory and cognitive performance: Memory Pharmaceuticals Corp. of Montvale, N.J.; Cortex Pharmaceuticals Inc. of Irvine; and Helicon Therapeutics Inc., founded by Tully, the geneticist at Cold Spring Harbor Laboratory.

All the new smart drugs are being developed as treatments for recognized illnesses such as Alzheimer's — a requirement for FDA approval. But the drug that will make a company and its stockholders rich will be the one that treats a disorder that until recently was not seen as an illness at all — "age-associated memory impairment," the mild but progressive forgetfulness that afflicts us all as we get older.

The risks involved
Neuroscientists say two factors could prevent Americans from succumbing completely to the seductions of smart pills. First, their performance may not live up to expectations. Second, they could have side effects, some of them difficult to predict.

"There's no free lunch," said Tully. Consumers will have to consider what level of discomfort or risk they're willing to accept in exchange for sharper recall or enhanced powers of concentration.

The side effect that most neuroscientists fear is not physical discomfort, but subtle mental change. Over time, a memory-enhancing drug might cause people to remember too much detail, cluttering the brain.

Similarly, a drug that sharpens attention might cause users to focus too intently on a particular task, failing to shift their attention in response to new developments.

In short, someone who notices or remembers everything may end up understanding nothing.

"The brain was designed by evolution over the millennia to be well-adapted because of the lives we lead," said Martha Farah, a psychologist at the University of Pennsylvania. "Our lives are better served by being able to focus on the essential information than being able to remember every little detail…. We meddle with these designs at our peril."

Despite such qualms, Farah is drawn to the idea that a mind enriched by a life of experience might not have to lose the speed of recall it enjoyed in its youth.

"To have the wisdom of age and the memory of a young person? That'd be a very good combination."


What's on the horizon?
Smart drugs will probably emerge from among medications developed for impairments of the brain and nervous system, including depression and schizophrenia, Alzheimer's disease and multiple sclerosis, stroke and spinal cord injury. Here are a few under development:


  • Are designed to amplify the strength of electrical signals between brain cells.
  • Could be the first of the new generation of cognitive enhancers to come to market; developed by Cortex Pharmaceuticals Inc., which has launched human trials.
  • One is being tested by the Pentagon as an antidote for sleep deprivation.
  • Boosted cognitive function of healthy Swedish medical students in a 1997 study.


Mem compounds

  • Are designed to strengthen consolidation of long-term memory — key to learning new skills.
  • Are under development by Memory Pharmaceuticals Corp., which has begun human testing on three separate Mem compounds as treatment for Alzheimer's disease, mild cognitive impairment and depression.
  • In early animal studies, one Mem compound appeared to restore the maze recall of middle-aged rats to youthful levels.
  • Could come to market by 2008.



  • Is designed to speed and strengthen the process by which short-term memories are committed to long-term storage.
  • Is under development by Helicon Therapeutics Inc., which plans to move from animal testing to trials on humans soon.
  • Shows particular promise as a drug to aid in the rehabilitation of stroke victims and to counter the effects of age-associated memory impairment.


Gene therapy

  • Genetically engineered cells are implanted deep inside the cortex, acting as a miniature biological pump that secretes nerve growth factor (NGF), a naturally occurring protein in all vertebrates.
  • Nerve growth factor revitalizes brain cells that atrophy and shrink as their host's age advances.
  • Biotechnology company Ceregene Inc. has launched early tests of the gene therapy on human subjects suffering from the early stages of Alzheimer's disease, in hopes of slowing its progress.
  • UC San Diego neuroscientist Mark Tuszynski, who designed the NGF-secreting pump, reported in 2000 that aged monkeys who got the implanted cells showed an almost complete restoration of normal cell function and size.


Source: LA Times
Date: 20 December 2004

By Melissa Healy, Times Staff Writer

Memory drugs create new ethical minefield

Move over, botox. Although injections of the most potent natural toxin known to science are marketed as knife-free plastic surgery to reduce wrinkles, Botox treatment is actually a neurological intervention. The toxin blocks the release of a neurochemical, acetylcholine, from neurons. That makes it the opening act in what promises -- or threatens -- to be a significant new drama. Welcome to "cosmetic neurology."

Sure, there have been reports over the years of, shall we say, recreational use of prescription pharmaceuticals. Some musicians and nervous public speakers take beta blockers (a heart drug) to vanquish stage fright. Modafinil (aka Provigil) is a stimulant approved for narcolepsy, but it has an underground following among those who want to feel as alert and rested after five hours of sleep as after eight. Ritalin, for attention-deficit hyperactivity disorder, improves concentration and the ability to plan, making it popular among healthy adults who simply want an edge in multitasking.

A string of recent discoveries, many of them from small studies that have flown under the radar, suggest that this is only the beginning. Ritalin, for instance, specifically boosts spatial working memory, or the ability to remember layouts and locations. Just the thing for back-country hikers, perhaps, or architects mentally juggling blueprints?

Compounds called cholinesterase inhibitors boost levels of the neurotransmitter acetylcholine, which lets neurons communicate with each other. One, donepezil (sold as Aricept), is approved for Alzheimer's disease. But that may be only one of its talents. In a 2002 study, scientists gave donepezil to one group of healthy, middle-age pilots and dummy pills to another. The donepezil group did markedly better learning maneuvers in a Cessna 172 simulator, particularly those used in flight emergencies.

Some drugs that affect memory work very selectively. So-called CREB inhibitors (CREB is a protein essential for incising memories in the brain) "seem to selectively erase only disturbing memories," says neurologist Anjan Chatterjee of the University of Pennsylvania, Philadelphia. And propanolol, a beta blocker, enhances the memory of events that are emotionally charged and that the brain otherwise suppresses. It also seems to erase the negative emotions associated with bad memories. Healthy people given the drug recall disturbing stories as if they were no more emotionally charged than a grocery list.

It's not that neuroscientists are deliberately looking for drugs that might be used for cosmetic neurology. Rather, these more frivolous uses are being discovered serendipitously, often in research on serious neurological diseases such as stroke. For instance, scientists find that small doses of amphetamines help stroke patients undergoing physical therapy relearn motor skills, such as tying shoes and using utensils, better and more quickly than with therapy alone. Taken half an hour before a therapy session, amphetamines seem to promote what's called neuroplasticity, the ability of the brain to form new connections or strengthen existing ones between its neurons. Those connections underlie both simple and complex sequences of movement.

"With amphetamines, the effects of therapy are more pronounced," says Dr. Chatterjee. "And animal studies suggest that pairing amphetamines with motor training leads to greater brain plasticity."

The day may be coming when perfectly healthy people will pop speed before a tennis lesson or piano instruction, knowing it may stimulate the brain rewiring that underlies a perfect backhand or a flawless "Fur Elise." Botox, after all, originally received government approval to treat two serious eye-muscle disorders, and now aging boomers regard a quick fix as no more momentous than a swipe of mascara. Cosmetic neurology could well follow the same arc, which means that the time for neurologists to weigh in on the ethical implications of all this is now.

Those implications are profound. If drugs can improve learning, make painful memories fade and sharpen attention, should physicians prescribe them? Must physicians prescribe them? Must patients -- perhaps pilots compelled by an employer -- take them? Might one airline distinguish itself from competitors by advertising its donepezil-taking crews?

Dr. Chatterjee captures the dilemma in a paper he wrote for the current issue of Neurology: "The distinction between therapy and enhancement can be vague, particularly when the notion of 'disease' lacks clear boundaries. ... If one purpose of medicine is to improve the quality of life of individuals who happen to be sick, then should medical knowledge be applied to those who happen to be healthy," lifting patients from normal functioning to enhanced functioning?

We can wring our hands all we want about pills that make learning more effective without greater effort, offending the belief that gains should be hard-earned, or about drugs that selectively erase painful memories, evoking a Brave New World of the happily drugged -- and less-than-fully human. I have a feeling it won't make much difference. "Patient" has become synonymous with "consumer," someone unlikely to take kindly to physicians, let alone ethicists, blocking his or her pursuit of self-improvement and happiness.



Source: The Wall Street Journal
Date: 1 October 2004